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Protein restriction and cancer
Accepted Manuscript Protein restriction and cancer
Jie Yin, Wenkai Ren, Xingguo Huang, Tiejun Li, Yulong Yin PII: DOI: Reference:
S0304-419X(18)30004-0 doi:10.1016/j.bbcan.2018.03.004 BBACAN 88211
To appear in: Received date: Revised date: Accepted date:
4 January 2018 2 March 2018 23 March 2018
Please cite this article as: Jie Yin, Wenkai Ren, Xingguo Huang, Tiejun Li, Yulong Yin , Protein restriction and cancer. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Bbacan(2018), doi:10.1016/ j.bbcan.2018.03.004
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ACCEPTED MANUSCRIPT Protein restriction and cancer Jie Yin1,2, Wenkai Ren3,4, Xingguo Huang5, Tiejun Li1,*, Yulong Yin1,*
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(1) Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences; Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture; Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha, P.R. China (2) University of Chinese Academy of Sciences, Beijing, P.R. China (3) Guangdong Provincial Key Laboratory of Animal Nutrition Control, Institute of Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, P.R. China (4) Jiangsu Co-Innovation Center for Important Animal Infectious Diseases and Zoonoses, Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, College of Veterinary Medicine, Yangzhou University, Yangzhou, P.R. China (5) Department of Animal science, Hunan Agriculture University, Changsha, P.R. China *Corresponding authors at: Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, P.R. China
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E-mail addresses: [email protected] (J. Yin), [email protected] (W.K. Ren), [email protected] (X.G. Huang), [email protected] (T.J. Li), [email protected] (Y.L. Yin)
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Abbreviations: PI3K, phosphoinositide 3-kinase; MAPK, mitogen activated protein kinase; mTORC1, mTOR complex 1; GCN2, general control nonderepressible 2; ULK, UNC-5 like autophagy activating kinase; ATG, autophagy related gene; GPCR, G protein coupled receptor; UCPs, uncoupling proteins; FGF21, fibroblast growth factor 21; Akt, protein kinase B; IGF-1R, insulin-like growth factor 1 receptor; IGF-1, insulin-like growth factor 1; mTOR, mammalian target of rapamycin; ATF4, targeting the activating transcription factor 4.
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Abstract: Protein restriction without malnutrition is currently an effective nutritional intervention known to prevent diseases and promote health span from yeast to human. Recently, low protein diets are reported to be associated with lowered cancer incidence and mortality risk of cancers in human. In murine models, protein restriction inhibits tumor growth via mTOR signaling pathway. IGF-1, amino acid metabolic programing, FGF21, and autophagy may also serve as potential mechanisms of protein restriction mediated cancer prevention. Together, dietary intervention aimed at reducing protein intake can be beneficial and has the potential to be widely adopted and effective in preventing and treating cancers. Keywords: Protein restriction / Cancer / Amino acid / IGF-1 / mTOR / FGF21 / Autophagy
1. Introduction
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Inconsistent with the highly regulated physiological processes in normal cells, cancer cells undergo an autonomous metabolic reprogramming to maintain rapid growth and proliferation and escape from growth suppressors and cell death signaling [1, 2]. Amino acids are one of the most abundant metabolic family that is involved in protein synthesis and physiological activities and dysfunction of amino acid metabolism is commonly seen in cancer patients [3, 4]. For example, taurine, glutamic acid, glycine, lysine, and ornithine are significantly altered in lung cancer tissues [5] and blood free amino acids are highly associated with lymph node metastases and clinical tumor markers in gastric and breast cancer patients. Amino acid uptake in the intestine contributes to the major sources of circulating amino acids and amino acid transporters are generally upregulated in tumor cells to maintain amino acid requirement [6]. Thus, amino acid metabolic phenotypes can be exploited to improve cancer screening, diagnosis, and treatment by targeting amino acid metabolic map or using nutritional interventions. In this frame, dietary regimens via protein restriction stands out as being deeply interconnected with reprograming metabolism of amino acids and stimulation of specific nutrient signaling pathways (i.e., IGF-1, mTOR, FGF21, and autophagy), which are associated with cancer metabolism, tumor growth, and overall mortality (Fig.1). This review builds on the increasingly sophisticated understanding of protein restriction and metabolic reprograming in cancers derived from work over the last decade. Our goal is to convey a nutritional potential via dietary protein restriction to improve cancer patient care. 2. Protein restriction and cancer Although studies on protein restriction mainly focus on aging and compelling evidence shows that low protein diets are positively associated with health span and lifespan [7-10], there is a renewed interest in the low protein diets with an increasing number of reports demonstrating direct connections among dietary protein restriction
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and cancers. The beneficial role of low protein diets in tumor growth and cancer outcomes has been observed in numerous studies. For example, Fontana et al. reported a 70% and 56 % inhibitory ratio of tumor growth in human xenograft models of prostate and breast cancer, respectively, after dietary a 7% protein diet when compared to an isocaloric 21% protein diet [11]. The tumor volume and growth rate of human breast cancer xenografts are also markedly reduced in mice fed a protein restricted diet, which shows a similar trend in an intermittent fasting model [12]. In clinical respondents aged 50~65 (n=6,381), high protein intake (20% or more of calories from proteins) results in a 4-fold increase in the risks of overall and cancer mortality compared with the low protein group (less than 10% of calories from proteins) during an 18 year follow up period [13], whereas low protein intake indicates lower cancer mortality. Meanwhile, the risks may be somewhat reduced if the dietary protein source does not come from animal protein [13], which is further validated in a mouse model that dietary 20% plant protein reduces tumor weight by 37% as compared to a 20% animal protein diet [11]. In addition, protein restriction has been reported to reduce cancer incidence. After implanting subcutaneously with 20,000 cells of murine breast cancer in mice, tumor incidence is only 70% at day 18 and 80% at day 39 post-implantation in the low protein (7%) group, while which is 100% at day 18 in the control group [13]. Although the mechanisms responsible for the protein restriction-mediated reduction in tumorigenesis have not been unequivocally identified, protein restriction exerts wide effects on cellular processes, including amino acid metabolism, energy metabolism, autophagy, inflammation, immune response, signaling pathways, and gut microbiota, which may be involved in protein restriction-induced epigenetic or metabolic changes. 3. Insulin-like growth factor 1 (IGF-1)
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IGF-1 signaling is one of the most investigated targets in cancers and mediates critical physiological processes in tumor cells, including carcinogenesis, angiogenesis, malignant cell proliferation, and metastatic growth of a variety of cancers [14-16]. To elicit growth or survival signaling, IGF-1 interacts with the cognate receptor, IGF-1R, that leads to proliferative and anti-apoptotic events [17, 18]. A recent meta-analysis including 10,554 prostate cancer cases and 13,618 control subjects reveals that circulating IGF-1 and IGFBP-3 concentrations are highly correlated with cancer risk [19]. From 2,253 clinic subjects aged 50~65, IGF-1 concentration shows a positive association with protein intake and the mortality risk of cancer increases an additional 9% in the high protein group for every 10 ng/ml increase in IGF-1 level [13], whereas reduction in IGF-1 level suggests a lower cancer incidence. Indeed, dietary a low protein diet for 4.4 ± 2.8 years in 53 ± 11 aged people shows low plasma growth factors and hormones, such as leptin, insulin, and IGFBP-3, which are highly linked to the increased risk of cancers [20]. In prostate cancer patients, one month of protein restriction increases leptin receptor and shifts the phosphorylation status of the insulin receptor signal transducer protein IRS1 [21]. Also, a decrease in IGF-1 level improves
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tumor chemosensitivity and protects against chemotoxicity in cancers [22], while short-term protein restriction fails to affect stress resistance and tumor progression in a subcutaneous glioma model although accompanying a lowered IGF-1 level [23], possibly because glioma is a particularly aggressive cancer and other cancer models should be further studied to evaluate the effect of protein restriction on chemotoxicity. Although the implication of IGF-1 and its receptor IGF-1R inactivation in protein restriction-mediated beneficial role in cancers is still obscure, various signaling nodes contribute to the potential mechanisms, such as the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) and mitogen activated protein kinase (MAPK) pathways [24]. PI3K/Akt and MAPK are two major downstream signals of IGF-1R and both Akt and MAPK mediate exogenous IGF-1-induced proliferation and survival in cancer cells [25]. Results from dietary restriction show that Akt and MAPK are highly associated with cancer metabolism [26, 27], which may participate in the sensitivities of tumors to low protein diets as dietary restriction and low protein diets generally confer a similar physiological functions.
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4. Amino acid metabolism and immune response in cancers
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In various models, protein restriction without malnutrition has been consistently identified to improve metabolic homeostasis and prevent disease development via metabolic reprogramming, especially for amino acid metabolism. Mirzaei et al. summarized that protein restriction inhibits phenylalanine, arginine, lysine, histone, methionine, tryptophan, leucine, isoleucine, and valine metabolism in yeast and flies models and shows an inverse correlation to risk of metabolic diseases [7]. Results from our previous study shows that dietary protein restriction markedly reduces muscle histone, arginine, valine, isoleucine, and tryptophan abundances in a pig model [28]. In clinic, plasma amino acid profiles differ from cancer types and areas (Table 1). For example, tryptophan, glycine, citrulline, ornithine, and proline are increased in lung cancer [5], while breast cancer patients have higher glutamate and histone concentrations [29]. Also, aspartate, glutamate, asparagine, serine, glycine, histone, taurine, tyrosine, valine, methione, lysine, isoleucine, leucine, and phenylalanine are gradually reduced from cervical intraepithelial neoplasia patients to invasive cancer [30]. Interestingly, blood histone, glutamine, tryptophan, and citrulline share a similar trend that these amino acids are decreased in almost all cancers, including lung cancer, gastric cancer, colorectal cancer, breast cancer, and prostate cancer (Table 1), indicating that histone, glutamine, tryptophan, and citrulline may be the highly required amino acids in cancers and targeting the metabolism of these amino acids may serve as a potential therapeutic method for cancer patients [31, 32]. In the tumor microenvironment, the immune responses is activated by specific recognition of cancer cells to produce immune-activating cytokines, while cancer cells hijack the adaptive immune response developed to inhibit inflammatory and immune responses [33, 34]. The amino acid metabolites in the tumor microenvironment, such as glutamine, tryptophan and succinate, highly shape the
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activation and differentiation of immune cells, like T cells and macrophages [35, 36]. For example, glutamine and leucine is essential for the activation of T cells and differentiation of Th1 cells and Th17 cells via mTOR signaling [37, 38], and serine is required for optimal T cell expansion through one-carbon metabolic network [39]. Tryptophan also contributes to exert the immune function of T cells, while upregulation of tryptophan degrading enzyme indoleamine 2,3-dioxygenase suppresses T-cell proliferation and activity [40, 41]. Arginine is critical for the activated T cells and is needed for the anti-tumor activity of T cells through associating with a shift from glycolysis to oxidative phosphorylation [42]. Recent investigations also highlight the regulatory functions of glutamine metabolism in macrophage phenotype and function: succinate from glutaminolysis promotes the activation of M1 macrophages [43], while α-ketoglutarate induces activation of M2 macrophages [44]. Thus, as certain amino acids play an important role in immune responses to clear cancerous cells by mediating the proliferation and differentiation of T cells as well as macrophages [45], amino acid metabolic reprogramming and immune response interaction may serve as a potential mechanism of nutritional interventions mediated cancer therapy. As different responses of amino acids to low protein diets and cancers, a central question remains: do all tumor types respond equally to protein restriction? Deregulation of amino acid metabolism is a common alteration seen in cancers but no literatures cover on amino acid metabolic reprograming in cancer patients by eating a low protein diet. Also, amino acids are highly required in cancer cells, how to provide amino acid substrates for immune function but not for cancer proliferation? Thus, a fuller mechanistic understanding of protein restriction/amino acid metabolism/immune function/specific cancer types will be important for efforts to exploit such alterations for personalized therapy in cancer patients. 5. PI3K/Akt/mTOR
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mTOR represents a key signaling node that senses amino acids and activated mTOR signaling has been noticed in various cancer models in response to proliferating signal by providing amino acid substrates and one-carbon units required for cancer metabolism [46-48]. mTOR also can be activated by the PI3K/Akt signaling cascade and PI3K/Akt aberration or mutations in various tumor types can be found in the data of The Cancer Genome Atlas (TCGA) consortium studies [49]. In cancers, the PI3K/Akt/mTOR pathway is initiated by transmembrane tyrosine kinase growth factor receptors, such as IGF-1R [50, 51]. Functional PI3K is translocated to the plasma membrane, ultimately leading to phosphorylation of Akt [52, 53]. Following PI3K pathway activation, Akt phosphorylates mTOR and enables signal propagation [50]. The crucial role of PI3K/Akt/mTOR in cancer cell biology has stimulated interest in signaling inactivation and various allosteric inhibitors in this pathway, such as temsirolimus and everolimus, have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treating cancers [49, 54].
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mTOR coordinates metabolic reprograming in low protein diets challenged models. Therefore, it is reasonable to speculate that mTOR serves as a potential mechanism for protein restriction in cancers. Indeed, dietary protein restriction inhibits the activity of the amino acid sensitive mTOR complex 1 (mTORC1) in cancer models [11, 12], which may further mediate cancer metabolism and tumor growth. Also, IGF-1 is decreased in response to dietary protein restriction [13, 22] and reduced IGF-1 is negatively associated with mTOR activation in cancers (Fig.1). For example, IGF-1 induces cell proliferation by up-regulating oncogenes (Snail and Slug) and the effect is abolished by inhibiting PI3K/Akt/mTOR signaling in ovarian cancer cells [50]. Meanwhile, mTOR has been reported to be a major regulatory node in the FGF21 signaling network [55], which is an independent prognostic biomarker of cancers .
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6. The biology of fibroblast growth factor 21 (FGF21)
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Recently, several groups unveil that FGF21 is an endocrine signal of metabolic response to dietary protein restriction [56, 57]. Consumption of a low protein diet markedly increases blood FGF21 concentrations in both rats and mice [58, 59]. Similar result is noticed in a human study that protein restriction for 28 days increases plasma FGF21 concentrations by 171% [58]. To investigate the source of the increased FGF21 level, Laeger and colleagues measured FGF21 expression in rat liver, adipose tissue, and skeletal muscle and found that FGF21 expression is markedly upregulated in the liver but not in the adipose tissue and skeletal muscle [58], suggesting that liver FGF21 expression mainly contributes to FGF21 response to low protein diets. Indeed, FGF21 deficient animals are fully resistant to low protein diets-induced metabolic changes compared with the wild-type mice [56, 58]. Studies focus on amino acid sensor general control nonderepressible 2 (GCN2) and uncoupling protein 1 (UCP1) further reveal the potential mechanisms of FGF21-dependent metabolic response to dietary protein restriction (Fig.1). GCN2 initially contributes to the induction of FGF21 by targeting the activating transcription factor 4 (ATF4) and induces FGF21 expression in protein restricted mice [56]. Also, UCP1 expression exhibits an FGF21-dependent manner and deletion of UCP1 blocks protein restriction-induced metabolic alterations [57]. Considering that FGF21 serves as an endocrine signal of metabolic responses to dietary protein restriction with beneficial influences on host metabolism, especially for glucose and amino acid metabolisms [60-62], one question may arise that does FGF21 contribute to the anticancer effect of protein restriction? The implication of FGF21 in protein restriction-mediated protection from cancers remains poorly understood and controversial. On the one hand, clinical data show that FGF21 level is significantly increased in cancer patients [63] and loss of FGF21 associates with cancerous hyper-proliferation and aberrant cancer signaling during hepatocellular carcinoma development [64]. On the other hand, FGF21 treatment or upregulation delays the initiatory effect of chemically induced hepatocarcinogenesis [65, 66]. In multiple regression analyses, circulating FGF21 concentration also shows a negative
ACCEPTED MANUSCRIPT association with IGF-1 in nondiabetic subjects [67]. In vitro and vivo models, FGF21 treatment or transgenic overexpression blunts IGF-1 signaling pathway [67-69], correlating with a low incidence of cancer. Therefore, although a consistent response to low protein diets is an increase in the FGF21 level and lowered levels of circulating IGF-1, protein restriction-mediated protective effects against tumors may implicate an enhancement of FGF21, but is obviously not limited to it. 7. Autophagy
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Protein restriction represents a critical gauge of amino acid availability to induce autophagy, which acts to release stored cellular substrates during nutrient restriction and maintains the normal cellular functions [70, 71]. Following 14 days of a low protein diet, liver autophagic makers (ATG5-ATG12 complex and LC3B) are markedly increased in rats and autophagy is highly associated with alterations in metabolic parameter [72]. Deficiency of autophagy exaggerates the adaptive changes in hepatic metabolism response to dietary a low-protein diet in BCL2-AAA mouse, which bear a genetic mutation that impairs autophagy induction [72]. Although the mechanism by how autophagy is initiated in response to dietary protein restriction is obscure, inactivated mTOR and reprogramed amino acid metabolism in cancers may potentiate to mediate autophagy in protein restricted conditions (Fig.1). mTORC1 has been widely demonstrated to inhibit autophagy process by targeting the autophagy-initiating UNC-5 like autophagy activating kinase (ULK) complex, autophagy related gene 13 (ATG13), ATG13, and FIP200 [73, 74]. Meanwhile, autophagy is specifically activated in response to amino acid starvation via mTORC1 and GCN2 signaling pathways [75]. Upstream signaling study unveils that extracellular amino acid availability is sensed by the cell surface G protein coupled receptor (GPCR) TAS1R1-TAS1R3 (T1R1-T1R3), which further activates mTORC1 and inhibits autophagy [76], whereas autophagy response is markedly enhanced in fasted TAS1R3 (-/-) mice [76]. In cancer biology, autophagy has been shown to exhibit opposing and context-dependent roles in cancers, including cytoprotective, cytotoxic, nonprotective, and cytostatic form of autophagy [77]. For more specific details of autophagy and cancers, readers are referred to recent reviews [77-79] and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. Additional studies are warranted to understand the exact manner in which protein restriction in cancer treatment is govern by mTOR and autophagy. 8. Conclusion Protein restriction without malnutrition has been consistently identified as effective strategies for preventing diseases and promoting health span from yeast to human [7, 80]. In cancers, dietary protein restriction remains a negative correlation with cancer incidence, tumor growth, and mortality risk [12, 13, 20]. Introduction of low protein diets represents a novel mean to pharmacologically reprogram cellular metabolism and could emerge as an important new nutritional strategy for preventing and treating
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diseases, such as cancers. However, caution must be exercised to avoid low protein diets in old people as aging turns the beneficial effects of protein restriction on mortality into negative effects with increased cancer and overall mortality in respondents over aged 65 [13]. The reason may be explained by that low protein diets fail to provide enough amino acids and become malnourished in older subjects with lowered absorbing and metabolic abilities. Thus, Levine and colleagues suggest that protein intake should be up to 1~1.3 grams of proteins/kg of body weigh/day from 0.7~0.8 grams of proteins/kg of body weigh/day recommended by the Food and Nutrition Board of the Institute of Medicine for up to aged 65 people [13]. Although the current results are inspiring, further studies should be investigated to confirm the mechanisms of protein restriction and metabolic reprograming in cancers. For example, protein restriction is highly associated with amino acid availability and metabolism, what is the detailed relationship between protein restriction mediated-amino acid response and amino acid metabolism in specific cancer patients? Protein restriction affects the metabolism of other nutrients (i.e., lipid and carbohydrate) [81-83], while the role of lipid and carbohydrate metabolism in protein restriction-mediated cancer biology is still obscure. Indeed, a low carbohydrate/high protein diet has been reported to slow tumor growth and prevent cancer initiation [84], suggesting that protein restriction-mediated cancer treatment is highly associated with nutritional ratio, which should be further studied to uncover the precision nutrition and molecular mechanisms in cancer therapy. Both FGF21 and autophagy are in response to dietary protein restriction and involved in cancers, direct evidence should be provided in cancer models under protein limited conditions to validate the role of FGF21 and autophagy in low protein diets-mediated cancer treatment. It is clear that no single pathway accounts for all the anticancer effects of low protein diets. Besides mTOR and IGF-1 signaling pathways, is there any other signaling events or factors involving protein restriction and cancer treatment? For example, dietary protein restriction rapidly and reproducibly shapes the gut microbiota communities and increasing evidence indicate a key role of microbiome in carcinogenesis [85-87], the mediatory role of gut microbiota in protein restriction-mediated cancer treatment need to be further investigated. In the coming years, studies of protein or amino acid restriction will surely uncover more surprises and signaling mechanisms to attenuate human diseases, such as cancers, diabetes, and obesity. Authorship contributions J. Yin, W.K. Ren, X.G. Huang, T.J. Li, and Y.L. Yin discussed the topic. JY drafted the manuscript. All authors revised and approved the final manuscript. Competing interests The authors declare that they have no competing interests.
ACCEPTED MANUSCRIPT Acknowledgements We are grateful to the Public Service Technology Center, Institute of Subtropical Agriculture, Chinese Academy of Sciences for technical support. Many thanks also to the editors and reviewers for the painstaking care taken in helping improve the clarity of the manuscript. Funding
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This study was supported by the National Basic Research Program of China (973) (2013CB127301), National Natural Science Foundation of China (No. 31472106), Hunan Key Research Program (2017NK2320), and China Agriculture Research System (CARS-35).
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References
[1] M.A. Dawson, The cancer epigenome: Concepts, challenges, and therapeutic opportunities, Science 355 (2017) 1147-1152. Cancer Biology, Cell 168 (2017) 657-669.
NU
[2] M.G. Vander Heiden, R.J. DeBerardinis, Understanding the Intersections between Metabolism and [3] J.R. Mayers, M.E. Torrence, L.V. Danai, T. Papagiannakopoulos, S.M. Davidson, M.R. Bauer, A.N.
MA
Lau, B.W. Ji, P.D. Dixit, A.M. Hosios, A. Muir, C.R. Chin, E. Freinkman, T. Jacks, B.M. Wolpin, D. Vitkup, M.G. Vander Heiden, Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers, Science 353 (2016) 1161-1165. [4] A. Hattori, T. Ito, Role of Amino Acid Metabolism in Cancer Progression, Exp. Hematol. 44 (2016)
D
S78-S78.
[5] Q.H. Zhao, Y. Cao, Y. Wang, C.L. Hu, A.L. Hu, L. Ruan, Q.L. Bo, Q.F. Liu, W.J. Chen, F.B. Tao, M.
PT E
Ren, Y.S. Ge, A.G. Chen, L. Li, Plasma and tissue free amino acid profiles and their concentration correlation in patients with lung cancer, Asia. Pac. J. Clin. Nutr. 23 (2014) 429-436. [6] Y.D. Bhutia, E. Babu, S. Ramachandran, V. Ganapathy, Amino Acid Transporters in Cancer and Their Relevance to "Glutamine Addiction": Novel Targets for the Design of a New Class of Anticancer
CE
Drugs, Cancer Res. 75 (2015) 1782-1788. [7] H. Mirzaei, J.A. Suarez, V.D. Longo, Protein and amino acid restriction, aging and disease: from yeast to humans, Trends Endocrin. Met. 25 (2014) 558-566.
AC
[8] H. Mirzaei, R. Raynes, V.D. Longo, The conserved role of protein restriction in aging and disease, Curr. Opin. Clin. Nutr. 19 (2016) 74-79. [9] D. Paddon-Jones, W.W. Campbell, P.F. Jacques, S.B. Kritchevsky, L.L. Moore, N.R. Rodriguez, L.J.C. van Loon, Protein and healthy aging, Am. J. Clin. Nutr. 101 (2015) 1339s-1345s. [10] S.J. Simpson, D.G. Le Couteur, D. Raubenheimer, S.M. Solon-Biet, G.J. Cooney, V.C. Cogger, L. Fontana, Dietary protein, aging and nutritional geometry, Ageing Res. Rev. 39 (2017) 78-86. [11] L. Fontana, R.M. Adelaiye, A.L. Rastelli, K.M. Miles, E. Ciamporcero, V.D. Longo, H. Nguyen, R. Vessella, R. Pili, Dietary protein restriction inhibits tumor growth in human xenograft models of prostate and breast cancer, Oncotarget 4 (2013) 2451-2461. [12] D.W. Lamming, N.E. Cummings, A.L. Rastelli, F. Gao, E. Cava, B. Bertozzi, F. Spelta, R. Pili, L. Fontana, Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model, Oncotarget 6 (2015) 31233-31240.
ACCEPTED MANUSCRIPT [13] M.E. Levine, J.A. Suarez, S. Brandhorst, P. Balasubramanian, C.W. Cheng, F. Madia, L. Fontana, M.G. Mirisola, J. Guevara-Aguirre, J. Wan, G. Passarino, B.K. Kennedy, M. Wei, P. Cohen, E.M. Crimmins, V.D. Longo, Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population, Cell Metab. 19 (2014) 407-417. [14] E. Sanchez-Lopez, E. Flashner-Abramson, S. Shalapour, Z. Zhong, K. Taniguchi, A. Levitzki, M. Karin, Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling, Oncogene 35 (2016) 2634-2644. [15] F. Hao, Q.H. Xu, J.V. Stevens, J. Sinnett-Smith, E. Rozengurt, Crosstalk between Insulin/Igf-1 Receptor and G Protein-Coupled Receptor (Gpcr) Signaling Pathways Stimulates Yap Function in
PT
Pancreatic Ductal Adenocarcinoma Cancer (Pdac) Cells, Gastroenterology 152 (2017) S802-S802. [16] Y.F. Zhou, S.X. Li, J.T. Li, D.F. Wan, Q.X. Li, Effect of microRNA-135a on Cell Proliferation,
RI
Migration, Invasion, Apoptosis and Tumor Angiogenesis Through the IGF-1/PI3K/Akt Signaling Pathway in Non-Small Cell Lung Cancer, Cell. Physiol. Biochem. 42 (2017) 1431-1446.
SC
[17] P.F. Christopoulos, A. Corthay, M. Koutsilieris, Aiming for the Insulin-like Growth Factor-1 system in breast cancer therapeutics, Cancer Treat. Rev. 63 (2017) 79-95. [18] W. Cai, M. Sakaguchi, A. Kleinridders, G. Gonzalez-Del Pino, J.M. Dreyfuss, B.T. O'Neill, A.K.
NU
Ramirez, H. Pan, J.N. Winnay, J. Boucher, M.J. Eck, C.R. Kahn, Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression, Nat. Commun. 8 (2017) 14892. [19] R.C. Travis, P.N. Appleby, R.M. Martin, J.M.P. Holly, D. Albanes, A. Black, H.B.
MA
Bueno-de-Mesquita, J.M. Chan, C. Chen, M.D. Chirlaque, M.B. Cook, M. Deschasaux, J.L. Donovan, L. Ferrucci, P. Galan, G.G. Giles, E.L. Giovannucci, M.J. Gunter, L.A. Habel, F.C. Hamdy, K.J. Helzlsouer, S. Hercberg, R.N. Hoover, J.A.M.J.L. Janssen, R. Kaaks, T. Kubo, L. Le Marchand, E.J. Metter, K. Mikami, J.K. Morris, D.E. Neal, M.L. Neuhouser, K. Ozasa, D. Palli, E.A. Platz, M.N.
D
Pollak, A.J. Price, M.J. Roobol, C. Schaefer, J.M. Schenk, G. Severi, M.J. Stampfer, P. Stattin, A. Tamakoshi, C.M. Tangen, M. Touvier, N.J. Wald, N.S. Weiss, R.G. Ziegler, T.J. Key, N.E. Allen, E.H.
PT E
Nutr, A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk, Cancer Res. 76 (2016) 2288-2300. [20] L. Fontana, S. Klein, J.O. Holloszy, Long-term low-protein, low-calorie diet and endurance 1456-1462.
CE
exercise modulate metabolic factors associated with cancer risk, Am. J. Clin. Nutr. 84 (2006) [21] E. Eitan, V. Tosti, C.N. Suire, E. Cava, S. Berkowitz, B. Bertozzi, S.M. Raefsky, N. Veronese, R. Spangler, F. Spelta, M. Mustapic, D. Kapogiannis, M.P. Mattson, L. Fontana, In a randomized trial in
AC
prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles, Aging Cell 16 (2017) 1430-1433. [22] C.H. Lee, F.M. Safdie, L. Raffaghello, M. Wei, F. Madia, E. Parrella, D. Hwang, P. Cohen, G. Bianchi, V.D. Longo, Reduced Levels of IGF-I Mediate Differential Protection of Normal and Cancer Cells in Response to Fasting and Improve Chemotherapeutic Index, Cancer Res. 70 (2010) 1564-1572. [23] S. Brandhorst, M. Wei, S. Hwang, T.E. Morgan, V.D. Longo, Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression, Exp. Gerontol. 48 (2013) 1120-1128. [24] P.F. Christopoulos, P. Msaouel, M. Koutsilieris, The role of the insulin-like growth factor-1 system in breast cancer, Mol. Cancer 14 (2015) 43. [25] H. Li, I.S. Batth, X. Qu, L. Xu, N. Song, R. Wang, Y. Liu, IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: overview and new insights, Mol. Cancer 16
ACCEPTED MANUSCRIPT (2017) 6. [26] O. Meynet, J.E. Ricci, Caloric restriction and cancer: molecular mechanisms and clinical implications, Trends Mol. Med. 20 (2014) 419-427. [27] J. Standard, Y. Jiang, M. Yu, X.Y. Su, Z.H. Zhao, J.T. Xu, J. Chen, B. King, L.Z. Lu, J. Tomich, R. Baybutt, W.Q. Wang, Reduced signaling of PI3K-Akt and RAS-MAPK pathways is the key target for weight-loss-induced cancer prevention by dietary calorie restriction and/or physical activity, J. Nutr. Biochem. 25 (2014) 1317-1323. [28] J. Yin, Y. Li, X. Zhu, H. Han, W. Ren, S. Chen, P. Bin, G. Liu, X. Huang, R. Fang, B. Wang, K. Wang, L. Sun, T. Li, Y. Yin, Effects of Long-Term Protein Restriction on Meat Quality, Muscle Amino
PT
Acids, and Amino Acid Transporters in Pigs, J. Agric. Food Chem. 65 (2017) 9297-9304. [29] T. Barnes, K. Bell, K.M. DiSebastiano, V. Vance, R. Hanning, C. Russell, J.A. Dubin, M. Bahl, N.
RI
Califaretti, C. Campbell, M. Mourtzakis, Plasma amino acid profiles of breast cancer patients early in the trajectory of the disease differ from healthy comparison groups, Appl. Physiol. Nutr. Metab. 39
SC
(2014) 740-744.
[30] A. Hasim, A. Aili, A. Maimaiti, B. Mamtimin, A. Abudula, H. Upur, Plasma-free amino acid profiling of cervical cancer and cervical intraepithelial neoplasia patients and its application for early
NU
detection, Mol. Biol. Rep. 40 (2013) 5853-5859.
[31] B.J. Altman, Z.E. Stine, C.V. Dang, From Krebs to clinic: glutamine metabolism to cancer therapy (vol 16, pg 619, 2016), Nat. Rev. Cancer 16 (2016) 773-773.
MA
[32] W.J. Huang, W. Choi, Y.L. Chen, Q. Zhang, H.T. Deng, W. He, Y.G. Shi, A proposed role for glutamine in cancer cell growth through acid resistance, Cell Res. 23 (2013) 724-727. [33] A. Ribas, Adaptive Immune Resistance: How Cancer Protects from Immune Attack, Cancer Discov. 5 (2015) 915-919.
D
[34] F. Marcucci, C. Rumio, A. Corti, Tumor cell-associated immune checkpoint molecules – Drivers of malignancy and stemness, BBA-Rev. Cancer 1868 (2017) 571-583.
PT E
[35] Y. He, M. Gao, Y. Cao, H. Tang, S. Liu, Y. Tao, Nuclear localization of metabolic enzymes in immunity and metastasis, BBA-Rev. Cancer 1868 (2017) 359-371. [36] C. Corbet, O. Feron, Cancer cell metabolism and mitochondria: Nutrient plasticity for TCA cycle fueling, BBA-Rev. Cancer 1868 (2017) 7-15.
CE
[37] M. Nakaya, Y. Xiao, X. Zhou, J.H. Chang, M. Chang, X. Cheng, M. Blonska, X. Lin, S.C. Sun, Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation, Immunity 40 (2014) 692-705.
AC
[38] L.V. Sinclair, J. Rolf, E. Emslie, Y.B. Shi, P.M. Taylor, D.A. Cantrell, Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation, Nat. Immunol. 14 (2013) 500-508. [39] E.H. Ma, G. Bantug, T. Griss, S. Condotta, R.M. Johnson, B. Samborska, N. Mainolfi, V. Suri, H. Guak, M.L. Balmer, M.J. Verway, T.C. Raissi, H. Tsui, G. Boukhaled, S. Henriques da Costa, C. Frezza, C.M. Krawczyk, A. Friedman, M. Manfredi, M.J. Richer, C. Hess, R.G. Jones, Serine Is an Essential Metabolite for Effector T Cell Expansion, Cell Metab. 25 (2017) 345-357. [40] J. Godin-Ethier, L.A. Hanafi, C.A. Piccirillo, R. Lapointe, Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic Perspectives, Clin. Cancer Res. 17 (2011) 6985-6991. [41] A. Amobi, F. Qian, A.A. Lugade, K. Odunsi, Tryptophan Catabolism and Cancer Immunotherapy Targeting IDO Mediated Immune Suppression, Adv. Exp. Med. Biol. 1036 (2017) 129-144.
ACCEPTED MANUSCRIPT [42] R. Geiger, J.C. Rieckmann, T. Wolf, C. Basso, Y. Feng, T. Fuhrer, M. Kogadeeva, P. Picotti, F. Meissner, M. Mann, N. Zamboni, F. Sallusto, A. Lanzavecchia, L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity, Cell 167 (2016) 829-842 e813. [43] G.M. Tannahill, A.M. Curtis, J. Adamik, E.M. Palsson-McDermott, A.F. McGettrick, G. Goel, C. Frezza, N.J. Bernard, B. Kelly, N.H. Foley, L. Zheng, A. Gardet, Z. Tong, S.S. Jany, S.C. Corr, M. Haneklaus, B.E. Caffrey, K. Pierce, S. Walmsley, F.C. Beasley, E. Cummins, V. Nizet, M. Whyte, C.T. Taylor, H. Lin, S.L. Masters, E. Gottlieb, V.P. Kelly, C. Clish, P.E. Auron, R.J. Xavier, L.A. O'Neill, Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha, Nature 496 (2013) 238-242.
PT
[44] P.S. Liu, H. Wang, X. Li, T. Chao, T. Teav, S. Christen, G. Di Conza, W.C. Cheng, C.H. Chou, M. Vavakova, C. Muret, K. Debackere, M. Mazzone, H.D. Huang, S.M. Fendt, J. Ivanisevic,
RI
α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming, Nat. Immunol. 18 (2017) 985-994.
SC
[45] A.K. Sikalidis, Amino Acids and Immune Response: A Role for Cysteine, Glutamine, Phenylalanine, Tryptophan and Arginine in T-cell Function and Cancer?, Pathol. Oncol. Res. 21 (2015) 9-17.
NU
[46] R.A. Saxton, D.M. Sabatini, mTOR Signaling in Growth, Metabolism, and Disease, Cell 168 (2017) 960-976.
[47] O. Leavy, NLRC3 inhibits mTOR in colorectal cancer, Nat. Rev. Immunol. 17 (2017) 79-79.
MA
[48] Y.Q. Zhang, P.K.S. Ng, M. Kucherlapati, F.J. Chen, Y.X. Liu, Y.H. Tsang, G. de Velasco, K.J. Jeong, R. Akbani, A. Hadjipanayis, A. Pantazi, C.A. Bristow, E. Lee, H.S. Mahadeshwar, J.B. Tang, J.H. Zhang, L.X. Yang, S. Seth, S. Lee, X.J. Ren, X.Z. Song, H.D. Sun, J. Seidman, L.J. Luquette, R.B. Xi, L. Chin, A. Protopopov, T.F. Westbrook, C.S. Shelley, T.K. Choueiri, M. Ittmann, C. Van Waes, J.N.
D
Weinstein, H. Liang, E.P. Henske, A.K. Godwin, P.J. Park, R. Kucherlapati, K.L. Scott, G.B. Mills, D.J. Kwiatkowski, C.J. Creighton, A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway
PT E
Alterations, Cancer Cell 31 (2017) 820-+.
[49] J. Polivka, Jr., F. Janku, Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway, Pharmacol. Ther. 142 (2014) 164-175.
[50] M.T. Lau, P.C. Leung, The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth
CE
factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells, Cancer Lett. 326 (2012) 191-198.
[51] M. Molina-Arcas, D.C. Hancock, C. Sheridan, M.S. Kumar, J. Downward, Coordinate Direct
AC
Input of Both KRAS and IGF1 Receptor to Activation of PI3 Kinase in KRAS-Mutant Lung Cancer, Cancer Discov. 3 (2013) 548-563. [52] I.A. Mayer, C.L. Arteaga, The PI3K/AKT Pathway as a Target for Cancer Treatment, Annu. Rev. Med. 67 (2016) 11-28. [53] S. Ebrahimi, M. Hosseini, S. Shahidsales, M. Maftouh, G.A. Ferns, M. Ghayour-Mobarhan, S.M. Hassanian, A. Avan, Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer, Curr. Med. Chem. 24 (2017) 1321-1331. [54] F. Chiarini, C. Evangelisti, J.A. McCubrey, A.M. Martelli, Current treatment strategies for inhibiting mTOR in cancer, Trends Pharmacol. Sci. 36 (2015) 124-135. [55] A.Y. Minard, S.X. Tan, P.Y. Yang, D.J. Fazakerley, W. Domanova, B.L. Parker, S.J. Humphrey, R. Jothi, J. Stockli, D.E. James, mTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes, Cell Rep. 17 (2016) 29-36.
ACCEPTED MANUSCRIPT [56] T. Laeger, D.C. Albarado, S.J. Burke, L. Trosclair, J.W. Hedgepeth, H.R. Berthoud, T.W. Gettys, J.J. Collier, H. Munzberg, C.D. Morrison, Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2, Cell Rep. 16 (2016) 707-716. [57] C.M. Hill, T. Laeger, D.C. Albarado, D.H. McDougal, H.R. Berthoud, H. Munzberg, C.D. Morrison, Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints, Sci. Rep. 7 (2017) 8209. [58] T. Laeger, T.M. Henagan, D.C. Albarado, L.M. Redman, G.A. Bray, R.C. Noland, H. Munzberg, S.M. Hutson, T.W. Gettys, M.W. Schwartz, C.D. Morrison, FGF21 is an endocrine signal of protein restriction, J. Clin. Invest. 124 (2014) 3913-3922.
PT
[59] K. Stemmer, F. Zani, K.M. Habegger, C. Neff, P. Kotzbeck, M. Bauer, S. Yalamanchilli, A. Azad, M. Lehti, P.J. Martins, T.D. Muller, P.T. Pfluger, R.J. Seeley, FGF21 is not required for glucose
RI
homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice, Diabetologia 58 (2015) 2414-2423.
SC
[60] T. Laeger, C. Baumeier, I. Wilhelmi, J. Wurfel, A. Kamitz, A. Schurmann, FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes, Diabetologia 60 (2017) 2274-2284.
NU
[61] T. Chalvon-Demersay, P.C. Even, D. Tome, C. Chaumontet, J. Piedcoq, C. Gaudichon, D. Azzout-Marniche, Low-protein diet induces, whereas high-protein diet reduces hepatic FGF21 production in mice, but glucose and not amino acids up-regulate FGF21 in cultured hepatocytes, J. Nutr.
MA
Biochem. 36 (2016) 60-67.
[62] M.J. Potthoff, Fgf21 and Metabolic Disease in 2016 a New Frontier in Fgf21 Biology, Nat. Rev. Endocrinol. 13 (2017) 74-76.
[63] M.E. Knott, J.N. Minatta, L. Roulet, G. Gueglio, L. Pasik, S.M. Ranuncolo, M. Nunez, L. Puricelli,
D
M.S. De Lorenzo, Circulating Fibroblast Growth Factor 21 (Fgf21) as Diagnostic and Prognostic Biomarker in Renal Cancer, J. Mol. Biomark. Diagn. 1 (2016) Suppl 2.
PT E
[64] Q. Zhang, Y. Li, T. Liang, X. Lu, X. Liu, C. Zhang, X. Jiang, R.C. Martin, M. Cheng, L. Cai, Loss of FGF21 in diabetic mouse during hepatocellular carcinogenetic transformation, Am. J. Cancer Res. 5 (2015) 1762-1774.
[65] X. Huang, C. Yu, C. Jin, C. Yang, R. Xie, D. Cao, F. Wang, W.L. McKeehan, Forced expression of fibroblast
CE
hepatocyte-specific
growth
factor
21
delays
initiation
of
chemically
induced
hepatocarcinogenesis, Mol. Carcinog. 45 (2006) 934-942. [66] P. Xu, Y. Zhang, W. Wang, Q. Yuan, Z. Liu, L.M. Rasoul, Q. Wu, M. Liu, X. Ye, D. Li, G. Ren,
AC
Long-Term Administration of Fibroblast Growth Factor 21 Prevents Chemically-Induced Hepatocarcinogenesis in Mice, Dig. Dis. Sci. 60 (2015) 3032-3043. [67] S. Kralisch, A. Tonjes, K. Krause, J. Richter, U. Lossner, P. Kovacs, T. Ebert, M. Bluher, M. Stumvoll, M. Fasshauer, Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans, J. Endocrinol. 216 (2013) 135-143. [68] Y. Zhang, Y. Xie, E.D. Berglund, K.C. Coate, T.T. He, T. Katafuchi, G. Xiao, M.J. Potthoff, W. Wei, Y. Wan, R.T. Yu, R.M. Evans, S.A. Kliewer, D.J. Mangelsdorf, The starvation hormone, fibroblast growth factor-21, extends lifespan in mice, Elife 1 (2012) e00065. [69] T. Inagaki, V.Y. Lin, R. Goetz, M. Mohammadi, D.J. Mangelsdorf, S.A. Kliewer, Inhibition of growth hormone signaling by the fasting-induced hormone FGF21, Cell Metab. 8 (2008) 77-83. [70] M. Kitada, Y. Ogura, T. Suzuki, S. Sen, S.M. Lee, K. Kanasaki, S. Kume, D. Koya, A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by
ACCEPTED MANUSCRIPT suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity, Diabetologia 59 (2016) 1307-1317. [71] H. Wang, G.J. Wilson, D. Zhou, S. Lezmi, X.W. Chen, D.K. Layman, Y.X. Pan, Induction of autophagy through the activating transcription factor 4 (ATF4)-dependent amino acid response pathway in maternal skeletal muscle may function as the molecular memory in response to gestational protein restriction to alert offspring to maternal nutrition, Brit. J. Nutr. 114 (2015) 519-532. [72] T.M. Henagan, T. Laeger, A.M. Navard, D. Albarado, R.C. Noland, K. Stadler, C.M. Elks, D. Burk, C.D. Morrison, Hepatic autophagy contributes to the metabolic response to dietary protein restriction, Metabolism 65 (2016) 805-815.
PT
[73] Z. Li, Y. Song, L. Liu, N. Hou, X. An, D. Zhan, Y. Li, L. Zhou, P. Li, L. Yu, J. Xia, Y. Zhang, J. Wang, X. Yang, miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR
RI
activation, Cell Death. Differ. 24 (2017) 1205-1213.
[74] S. Ruf, A.M. Heberle, M. Langelaar-Makkinje, S. Gelino, D. Wilkinson, C. Gerbeth, J.J. Schwarz,
SC
B. Holzwarth, B. Warscheid, C. Meisinger, M.A.T.M. van Vugt, R. Baumeister, M. Hansen, K. Thedieck, PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy, Autophagy 13 (2017) 486-505.
NU
[75] B. Carroll, V.I. Korolchuk, S. Sarkar, Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis, Amino Acids 47 (2015) 2065-2088. [76] E.M. Wauson, E. Zaganjor, M.H. Cobb, Amino acid regulation of autophagy through the GPCR
MA
TAS1R1-TAS1R3, Autophagy 9 (2013) 418-419.
[77] D.A. Gewirtz, The four faces of autophagy: implications for cancer therapy, Cancer Res. 74 (2014) 647-651.
[78] J.M.M. Levy, C.G. Towers, A. Thorburn, Targeting autophagy in cancer, Nat. Rev. Cancer 17
D
(2017) 528-542.
[79] E. White, The role for autophagy in cancer, J. Clin. Invest. 125 (2015) 42-46.
PT E
[80] H. Mirzaei, R. Raynes, V.D. Longo, The conserved role of protein restriction in aging and disease, Curr. Opin. Clin. Nutr. Metab. Care 19 (2016) 74-79. [81] A.P. Martins, P.A. Lopes, M.S. Madeira, S.V. Martins, N.C. Santos, T.F. Moura, J.A. Prates, G. Soveral, Differences in lipid deposition and adipose membrane biophysical properties from lean and
CE
obese pigs under dietary protein restriction, Biochem. Biophys. Res. Commun. 423 (2012) 170-175. [82] S.M. Solon-Biet, S.J. Mitchell, S.C. Coogan, V.C. Cogger, R. Gokarn, A.C. McMahon, D. Raubenheimer, R. de Cabo, S.J. Simpson, D.G. Le Couteur, Dietary Protein to Carbohydrate Ratio and
AC
Caloric Restriction: Comparing Metabolic Outcomes in Mice, Cell Rep. 11 (2015) 1529-1534. [83] L. Zitvogel, F. Pietrocola, G. Kroemer, Nutrition, inflammation and cancer, Nat. Immunol. 18 (2017) 843-850.
[84] V.W. Ho, K. Leung, A. Hsu, B. Luk, J. Lai, S.Y. Shen, A.I. Minchinton, D. Waterhouse, M.B. Bally, W. Lin, B.H. Nelson, L.M. Sly, G. Krystal, A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation, Cancer Res. 71 (2011) 4484-4493. [85] W.S. Garrett, Cancer and the microbiota, Science 348 (2015) 80-86. [86] L. Zitvogel, M. Ayyoub, B. Routy, G. Kroemer, Microbiome and Anticancer Immunosurveillance, Cell 165 (2016) 276-287. [87] T.A. Scott, L.M. Quintaneiro, P. Norvaisas, P.P. Lui, M.P. Wilson, K.Y. Leung, L. Herrera-Dominguez, S. Sudiwala, A. Pessia, P.T. Clayton, K. Bryson, V. Velagapudi, P.B. Mills, A. Typas, N.D.E. Greene, F. Cabreiro, Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C.
ACCEPTED MANUSCRIPT elegans, Cell 169 (2017) 442-456 e418. [88] A.M. Proenza, J. Oliver, A. Palou, P. Roca, Breast and lung cancer are associated with a decrease in blood cell amino acid content, J. Nutr. Biochem. 14 (2003) 133-138. [89] M. Shingyoji, T. Iizasa, M. Higashiyama, F. Imamura, N. Saruki, A. Imaizumi, H. Yamamoto, T. Daimon, O. Tochikubo, T. Mitsushima, M. Yamakado, H. Kimura, The significance and robustness of a plasma free amino acid (PFAA) profile-based multiplex function for detecting lung cancer, BMC cancer 13 (2013) 77. [90] Y. Miyagi, M. Higashiyama, A. Gochi, M. Akaike, T. Ishikawa, T. Miura, N. Saruki, E. Bando, H. Kimura, F. Imamura, M. Moriyama, I. Ikeda, A. Chiba, F. Oshita, A. Imaizumi, H. Yamamoto, H.
PT
Miyano, K. Horimoto, O. Tochikubo, T. Mitsushima, M. Yamakado, N. Okamoto, Plasma free amino acid profiling of five types of cancer patients and its application for early detection, PLoS One 6 (2011)
RI
e24143.
[91] H.J. Kim, S.H. Jang, J.S. Ryu, J.E. Lee, Y.C. Kim, M.K. Lee, T.W. Jang, S.Y. Lee, H. Nakamura,
SC
N. Nishikata, M. Mori, Y. Noguchi, H. Miyano, K.Y. Lee, The performance of a novel amino acid multivariate index for detecting lung cancer: A case control study in Korea, Lung Cancer 90 (2015) 522-527.
NU
[92] A. Klupczynska, P. Derezinski, W. Dyszkiewicz, K. Pawlak, M. Kasprzyk, Z.J. Kokot, Evaluation of serum amino acid profiles' utility in non-small cell lung cancer detection in Polish population, Lung Cancer 100 (2016) 71-76.
MA
[93] Y. Gu, T.X. Chen, S.Z. Fu, X. Sun, L.Y. Wang, J. Wang, Y.F. Lu, S.M. Ding, G.D. Ruan, L.S. Teng, M. Wang, Perioperative dynamics and significance of amino acid profiles in patients with cancer, J. Transl. Med. 13 (2015).
[94] P. Derezinski, A. Klupczynska, W. Sawicki, J.A. Palka, Z.J. Kokot, Amino Acid Profiles of Serum
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and Urine in Search for Prostate Cancer Biomarkers: a Pilot Study, Int. J. Med. Sci. 14 (2017) 1-12.
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Figure legends Fig.1 Working model of protein restriction in cancers. Five pathways are mainly involved in the mechanism of protein restriction in cancers, including FGF21, IGF-1, mTOR, amino acid reprograming, and autophagy. Abbreviations: AA, amino acids; PI3K, phosphoinositide 3-kinase; GCN2, general control nonderepressible 2; UCPs, uncoupling proteins; FGF21, fibroblast growth factor 21; Akt, protein kinase B; IGF-1R, insulin-like growth factor 1 receptor; IGF-1, insulin-like growth factor 1; mTOR, mammalian target of rapamycin.
ACCEPTED MANUSCRIPT Table 1 Amino acid changes in cancer patients. Abbreviations: AA, amino acids; NSCLC, non-small cell lung cancer; Glu, glutamate; Asp, aspartate; Cys, cysteine; Cit, Citrulline; Orn, ornithine; Ala, alanine (Ala); Arg, arginine; Asn, asparagine; Gln, glutamine; Gly, glycine; His, histidine; Ile, isoleucine; Leu, leucine; Lys, lysine; Met, methionine; Phe, phenylalanine; Pro, proline; Ser, serine; Thr, threonine; Trp, tryptophan; Tyr, tyrosine (Tyr); Val, valine. Country
Cases
Increased AA
Decreased AA
Ref
Lung cancer
China
27
Blood: Phe
Blood: Trp, Gly, Cit, Orn, and Pro
[5]
Cancer tissue: Tau,
Cancer tissue: Lys and Orn
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Cancer type
Glu, and Gly Spain
14
Lung Cancer
Japan
171
Blood: Val and Pro
[88]
Blood: Pro, Val, Ile,
Blood: Asn, Gln, Ala, Cit, Met, His, and
[89]
Leu, Tyr, Phe, and
Trp,
Lung cancer
Japan
200
Blood:
Ser,
Pro,
Gly, Met, Ile, Leu,
Lung cancer
Korean
Blood: Asn, Gln, Cit, His, Trp, and Orn
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and Phe
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Orn,
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Lung cancer
75
Blood: Thr, Asn, Gln, Gly, Ala, Cit, Val,
[90]
[91]
Met, Leu, His, Trp, Lys, and Arg
Poland
90
patients
Blood: β-Ala and Phe
China
199
56
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Gastric cancer
Japan
Blood:
Thr,
Cys,
and Arg
Colorectal
Japan
[92]
Blood: Thr, Asn, Gln, Ala, Cit, Val,
[90]
Met, Ile, Leu, Tyr, Phe, His, Trp, Lys,
Blood: Asp, Ser, Glu, Gly, Ala, Val,
[93]
Lys, His, and Pro
199
Blood: Thr, Asn, Gln, Cit, Val, Met,
[90]
Leu, Tyr, Phe, His, Trp, Orn, Lys, and Arg
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cancer
Blood: Ala, Arg, Asp, Cit, Pro, and Ser
and Arg
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Gastric cancer
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NSCLC
Blood:
Breast cancer
China
28
Blood: Thr and Arg
Breast cancer
Spain
16
Breast cancer
Canada
8
Blood: Glu and His
Blood: Thr
[29]
Thyroid cancer
China
33
Blood:
Blood: Asp, Glu, Gly, and Pro
[93]
Blood: Asp, Glu, Ser, Gly, His, Tau,
[30]
Japan
AC
Breast cancer
196
Thr,
Ser,
Blood: Gln, Pro, Tyr, Phe, His, and Trp
[90]
Blood: Asp, Glu, and Gly,
[93]
Blood: Asp and Glu
[88]
Gly, Ala, Orn, and Lys
Thr,
Met,
Leu, Tyr, Lys, and Arg Cervical
China
26
Blood: Arg and Thr
intraepithelial
Ala, Pro, Tyr, Val, Met, Lys, Ile, Leu,
neoplasia
and Phe,
Prostate cancer
Poland
49
Blood: Arg, Asp,
Blood: Ala, Glu, Gln, His, Ile, Leu, Lys,
and β-Ala
Met, and Phe,
Urine: Tau
Urine: Arg, Cit, Cys, Glu, Gln, His, Ile,
[94 ]
ACCEPTED MANUSCRIPT Leu, Lys, Met, Orn, Phe, Ser, Trp, and Tyr Prostate cancer
Japan
134
Blood:
Ala,
Orn,
Blood: Gln, Val, Leu, Trp, and Arg
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[90]
Figure 1
Jie Yin, Wenkai Ren, Xingguo Huang, Tiejun Li, Yulong Yin PII: DOI: Reference:
S0304-419X(18)30004-0 doi:10.1016/j.bbcan.2018.03.004 BBACAN 88211
To appear in: Received date: Revised date: Accepted date:
4 January 2018 2 March 2018 23 March 2018
Please cite this article as: Jie Yin, Wenkai Ren, Xingguo Huang, Tiejun Li, Yulong Yin , Protein restriction and cancer. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Bbacan(2018), doi:10.1016/ j.bbcan.2018.03.004
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ACCEPTED MANUSCRIPT Protein restriction and cancer Jie Yin1,2, Wenkai Ren3,4, Xingguo Huang5, Tiejun Li1,*, Yulong Yin1,*
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(1) Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences; Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture; Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha, P.R. China (2) University of Chinese Academy of Sciences, Beijing, P.R. China (3) Guangdong Provincial Key Laboratory of Animal Nutrition Control, Institute of Subtropical Animal Nutrition and Feed, College of Animal Science, South China Agricultural University, Guangzhou, P.R. China (4) Jiangsu Co-Innovation Center for Important Animal Infectious Diseases and Zoonoses, Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, College of Veterinary Medicine, Yangzhou University, Yangzhou, P.R. China (5) Department of Animal science, Hunan Agriculture University, Changsha, P.R. China *Corresponding authors at: Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, P.R. China
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E-mail addresses: [email protected] (J. Yin), [email protected] (W.K. Ren), [email protected] (X.G. Huang), [email protected] (T.J. Li), [email protected] (Y.L. Yin)
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Abbreviations: PI3K, phosphoinositide 3-kinase; MAPK, mitogen activated protein kinase; mTORC1, mTOR complex 1; GCN2, general control nonderepressible 2; ULK, UNC-5 like autophagy activating kinase; ATG, autophagy related gene; GPCR, G protein coupled receptor; UCPs, uncoupling proteins; FGF21, fibroblast growth factor 21; Akt, protein kinase B; IGF-1R, insulin-like growth factor 1 receptor; IGF-1, insulin-like growth factor 1; mTOR, mammalian target of rapamycin; ATF4, targeting the activating transcription factor 4.
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Abstract: Protein restriction without malnutrition is currently an effective nutritional intervention known to prevent diseases and promote health span from yeast to human. Recently, low protein diets are reported to be associated with lowered cancer incidence and mortality risk of cancers in human. In murine models, protein restriction inhibits tumor growth via mTOR signaling pathway. IGF-1, amino acid metabolic programing, FGF21, and autophagy may also serve as potential mechanisms of protein restriction mediated cancer prevention. Together, dietary intervention aimed at reducing protein intake can be beneficial and has the potential to be widely adopted and effective in preventing and treating cancers. Keywords: Protein restriction / Cancer / Amino acid / IGF-1 / mTOR / FGF21 / Autophagy
1. Introduction
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Inconsistent with the highly regulated physiological processes in normal cells, cancer cells undergo an autonomous metabolic reprogramming to maintain rapid growth and proliferation and escape from growth suppressors and cell death signaling [1, 2]. Amino acids are one of the most abundant metabolic family that is involved in protein synthesis and physiological activities and dysfunction of amino acid metabolism is commonly seen in cancer patients [3, 4]. For example, taurine, glutamic acid, glycine, lysine, and ornithine are significantly altered in lung cancer tissues [5] and blood free amino acids are highly associated with lymph node metastases and clinical tumor markers in gastric and breast cancer patients. Amino acid uptake in the intestine contributes to the major sources of circulating amino acids and amino acid transporters are generally upregulated in tumor cells to maintain amino acid requirement [6]. Thus, amino acid metabolic phenotypes can be exploited to improve cancer screening, diagnosis, and treatment by targeting amino acid metabolic map or using nutritional interventions. In this frame, dietary regimens via protein restriction stands out as being deeply interconnected with reprograming metabolism of amino acids and stimulation of specific nutrient signaling pathways (i.e., IGF-1, mTOR, FGF21, and autophagy), which are associated with cancer metabolism, tumor growth, and overall mortality (Fig.1). This review builds on the increasingly sophisticated understanding of protein restriction and metabolic reprograming in cancers derived from work over the last decade. Our goal is to convey a nutritional potential via dietary protein restriction to improve cancer patient care. 2. Protein restriction and cancer Although studies on protein restriction mainly focus on aging and compelling evidence shows that low protein diets are positively associated with health span and lifespan [7-10], there is a renewed interest in the low protein diets with an increasing number of reports demonstrating direct connections among dietary protein restriction
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and cancers. The beneficial role of low protein diets in tumor growth and cancer outcomes has been observed in numerous studies. For example, Fontana et al. reported a 70% and 56 % inhibitory ratio of tumor growth in human xenograft models of prostate and breast cancer, respectively, after dietary a 7% protein diet when compared to an isocaloric 21% protein diet [11]. The tumor volume and growth rate of human breast cancer xenografts are also markedly reduced in mice fed a protein restricted diet, which shows a similar trend in an intermittent fasting model [12]. In clinical respondents aged 50~65 (n=6,381), high protein intake (20% or more of calories from proteins) results in a 4-fold increase in the risks of overall and cancer mortality compared with the low protein group (less than 10% of calories from proteins) during an 18 year follow up period [13], whereas low protein intake indicates lower cancer mortality. Meanwhile, the risks may be somewhat reduced if the dietary protein source does not come from animal protein [13], which is further validated in a mouse model that dietary 20% plant protein reduces tumor weight by 37% as compared to a 20% animal protein diet [11]. In addition, protein restriction has been reported to reduce cancer incidence. After implanting subcutaneously with 20,000 cells of murine breast cancer in mice, tumor incidence is only 70% at day 18 and 80% at day 39 post-implantation in the low protein (7%) group, while which is 100% at day 18 in the control group [13]. Although the mechanisms responsible for the protein restriction-mediated reduction in tumorigenesis have not been unequivocally identified, protein restriction exerts wide effects on cellular processes, including amino acid metabolism, energy metabolism, autophagy, inflammation, immune response, signaling pathways, and gut microbiota, which may be involved in protein restriction-induced epigenetic or metabolic changes. 3. Insulin-like growth factor 1 (IGF-1)
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IGF-1 signaling is one of the most investigated targets in cancers and mediates critical physiological processes in tumor cells, including carcinogenesis, angiogenesis, malignant cell proliferation, and metastatic growth of a variety of cancers [14-16]. To elicit growth or survival signaling, IGF-1 interacts with the cognate receptor, IGF-1R, that leads to proliferative and anti-apoptotic events [17, 18]. A recent meta-analysis including 10,554 prostate cancer cases and 13,618 control subjects reveals that circulating IGF-1 and IGFBP-3 concentrations are highly correlated with cancer risk [19]. From 2,253 clinic subjects aged 50~65, IGF-1 concentration shows a positive association with protein intake and the mortality risk of cancer increases an additional 9% in the high protein group for every 10 ng/ml increase in IGF-1 level [13], whereas reduction in IGF-1 level suggests a lower cancer incidence. Indeed, dietary a low protein diet for 4.4 ± 2.8 years in 53 ± 11 aged people shows low plasma growth factors and hormones, such as leptin, insulin, and IGFBP-3, which are highly linked to the increased risk of cancers [20]. In prostate cancer patients, one month of protein restriction increases leptin receptor and shifts the phosphorylation status of the insulin receptor signal transducer protein IRS1 [21]. Also, a decrease in IGF-1 level improves
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tumor chemosensitivity and protects against chemotoxicity in cancers [22], while short-term protein restriction fails to affect stress resistance and tumor progression in a subcutaneous glioma model although accompanying a lowered IGF-1 level [23], possibly because glioma is a particularly aggressive cancer and other cancer models should be further studied to evaluate the effect of protein restriction on chemotoxicity. Although the implication of IGF-1 and its receptor IGF-1R inactivation in protein restriction-mediated beneficial role in cancers is still obscure, various signaling nodes contribute to the potential mechanisms, such as the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) and mitogen activated protein kinase (MAPK) pathways [24]. PI3K/Akt and MAPK are two major downstream signals of IGF-1R and both Akt and MAPK mediate exogenous IGF-1-induced proliferation and survival in cancer cells [25]. Results from dietary restriction show that Akt and MAPK are highly associated with cancer metabolism [26, 27], which may participate in the sensitivities of tumors to low protein diets as dietary restriction and low protein diets generally confer a similar physiological functions.
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4. Amino acid metabolism and immune response in cancers
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In various models, protein restriction without malnutrition has been consistently identified to improve metabolic homeostasis and prevent disease development via metabolic reprogramming, especially for amino acid metabolism. Mirzaei et al. summarized that protein restriction inhibits phenylalanine, arginine, lysine, histone, methionine, tryptophan, leucine, isoleucine, and valine metabolism in yeast and flies models and shows an inverse correlation to risk of metabolic diseases [7]. Results from our previous study shows that dietary protein restriction markedly reduces muscle histone, arginine, valine, isoleucine, and tryptophan abundances in a pig model [28]. In clinic, plasma amino acid profiles differ from cancer types and areas (Table 1). For example, tryptophan, glycine, citrulline, ornithine, and proline are increased in lung cancer [5], while breast cancer patients have higher glutamate and histone concentrations [29]. Also, aspartate, glutamate, asparagine, serine, glycine, histone, taurine, tyrosine, valine, methione, lysine, isoleucine, leucine, and phenylalanine are gradually reduced from cervical intraepithelial neoplasia patients to invasive cancer [30]. Interestingly, blood histone, glutamine, tryptophan, and citrulline share a similar trend that these amino acids are decreased in almost all cancers, including lung cancer, gastric cancer, colorectal cancer, breast cancer, and prostate cancer (Table 1), indicating that histone, glutamine, tryptophan, and citrulline may be the highly required amino acids in cancers and targeting the metabolism of these amino acids may serve as a potential therapeutic method for cancer patients [31, 32]. In the tumor microenvironment, the immune responses is activated by specific recognition of cancer cells to produce immune-activating cytokines, while cancer cells hijack the adaptive immune response developed to inhibit inflammatory and immune responses [33, 34]. The amino acid metabolites in the tumor microenvironment, such as glutamine, tryptophan and succinate, highly shape the
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activation and differentiation of immune cells, like T cells and macrophages [35, 36]. For example, glutamine and leucine is essential for the activation of T cells and differentiation of Th1 cells and Th17 cells via mTOR signaling [37, 38], and serine is required for optimal T cell expansion through one-carbon metabolic network [39]. Tryptophan also contributes to exert the immune function of T cells, while upregulation of tryptophan degrading enzyme indoleamine 2,3-dioxygenase suppresses T-cell proliferation and activity [40, 41]. Arginine is critical for the activated T cells and is needed for the anti-tumor activity of T cells through associating with a shift from glycolysis to oxidative phosphorylation [42]. Recent investigations also highlight the regulatory functions of glutamine metabolism in macrophage phenotype and function: succinate from glutaminolysis promotes the activation of M1 macrophages [43], while α-ketoglutarate induces activation of M2 macrophages [44]. Thus, as certain amino acids play an important role in immune responses to clear cancerous cells by mediating the proliferation and differentiation of T cells as well as macrophages [45], amino acid metabolic reprogramming and immune response interaction may serve as a potential mechanism of nutritional interventions mediated cancer therapy. As different responses of amino acids to low protein diets and cancers, a central question remains: do all tumor types respond equally to protein restriction? Deregulation of amino acid metabolism is a common alteration seen in cancers but no literatures cover on amino acid metabolic reprograming in cancer patients by eating a low protein diet. Also, amino acids are highly required in cancer cells, how to provide amino acid substrates for immune function but not for cancer proliferation? Thus, a fuller mechanistic understanding of protein restriction/amino acid metabolism/immune function/specific cancer types will be important for efforts to exploit such alterations for personalized therapy in cancer patients. 5. PI3K/Akt/mTOR
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mTOR represents a key signaling node that senses amino acids and activated mTOR signaling has been noticed in various cancer models in response to proliferating signal by providing amino acid substrates and one-carbon units required for cancer metabolism [46-48]. mTOR also can be activated by the PI3K/Akt signaling cascade and PI3K/Akt aberration or mutations in various tumor types can be found in the data of The Cancer Genome Atlas (TCGA) consortium studies [49]. In cancers, the PI3K/Akt/mTOR pathway is initiated by transmembrane tyrosine kinase growth factor receptors, such as IGF-1R [50, 51]. Functional PI3K is translocated to the plasma membrane, ultimately leading to phosphorylation of Akt [52, 53]. Following PI3K pathway activation, Akt phosphorylates mTOR and enables signal propagation [50]. The crucial role of PI3K/Akt/mTOR in cancer cell biology has stimulated interest in signaling inactivation and various allosteric inhibitors in this pathway, such as temsirolimus and everolimus, have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treating cancers [49, 54].
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mTOR coordinates metabolic reprograming in low protein diets challenged models. Therefore, it is reasonable to speculate that mTOR serves as a potential mechanism for protein restriction in cancers. Indeed, dietary protein restriction inhibits the activity of the amino acid sensitive mTOR complex 1 (mTORC1) in cancer models [11, 12], which may further mediate cancer metabolism and tumor growth. Also, IGF-1 is decreased in response to dietary protein restriction [13, 22] and reduced IGF-1 is negatively associated with mTOR activation in cancers (Fig.1). For example, IGF-1 induces cell proliferation by up-regulating oncogenes (Snail and Slug) and the effect is abolished by inhibiting PI3K/Akt/mTOR signaling in ovarian cancer cells [50]. Meanwhile, mTOR has been reported to be a major regulatory node in the FGF21 signaling network [55], which is an independent prognostic biomarker of cancers .
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6. The biology of fibroblast growth factor 21 (FGF21)
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Recently, several groups unveil that FGF21 is an endocrine signal of metabolic response to dietary protein restriction [56, 57]. Consumption of a low protein diet markedly increases blood FGF21 concentrations in both rats and mice [58, 59]. Similar result is noticed in a human study that protein restriction for 28 days increases plasma FGF21 concentrations by 171% [58]. To investigate the source of the increased FGF21 level, Laeger and colleagues measured FGF21 expression in rat liver, adipose tissue, and skeletal muscle and found that FGF21 expression is markedly upregulated in the liver but not in the adipose tissue and skeletal muscle [58], suggesting that liver FGF21 expression mainly contributes to FGF21 response to low protein diets. Indeed, FGF21 deficient animals are fully resistant to low protein diets-induced metabolic changes compared with the wild-type mice [56, 58]. Studies focus on amino acid sensor general control nonderepressible 2 (GCN2) and uncoupling protein 1 (UCP1) further reveal the potential mechanisms of FGF21-dependent metabolic response to dietary protein restriction (Fig.1). GCN2 initially contributes to the induction of FGF21 by targeting the activating transcription factor 4 (ATF4) and induces FGF21 expression in protein restricted mice [56]. Also, UCP1 expression exhibits an FGF21-dependent manner and deletion of UCP1 blocks protein restriction-induced metabolic alterations [57]. Considering that FGF21 serves as an endocrine signal of metabolic responses to dietary protein restriction with beneficial influences on host metabolism, especially for glucose and amino acid metabolisms [60-62], one question may arise that does FGF21 contribute to the anticancer effect of protein restriction? The implication of FGF21 in protein restriction-mediated protection from cancers remains poorly understood and controversial. On the one hand, clinical data show that FGF21 level is significantly increased in cancer patients [63] and loss of FGF21 associates with cancerous hyper-proliferation and aberrant cancer signaling during hepatocellular carcinoma development [64]. On the other hand, FGF21 treatment or upregulation delays the initiatory effect of chemically induced hepatocarcinogenesis [65, 66]. In multiple regression analyses, circulating FGF21 concentration also shows a negative
ACCEPTED MANUSCRIPT association with IGF-1 in nondiabetic subjects [67]. In vitro and vivo models, FGF21 treatment or transgenic overexpression blunts IGF-1 signaling pathway [67-69], correlating with a low incidence of cancer. Therefore, although a consistent response to low protein diets is an increase in the FGF21 level and lowered levels of circulating IGF-1, protein restriction-mediated protective effects against tumors may implicate an enhancement of FGF21, but is obviously not limited to it. 7. Autophagy
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Protein restriction represents a critical gauge of amino acid availability to induce autophagy, which acts to release stored cellular substrates during nutrient restriction and maintains the normal cellular functions [70, 71]. Following 14 days of a low protein diet, liver autophagic makers (ATG5-ATG12 complex and LC3B) are markedly increased in rats and autophagy is highly associated with alterations in metabolic parameter [72]. Deficiency of autophagy exaggerates the adaptive changes in hepatic metabolism response to dietary a low-protein diet in BCL2-AAA mouse, which bear a genetic mutation that impairs autophagy induction [72]. Although the mechanism by how autophagy is initiated in response to dietary protein restriction is obscure, inactivated mTOR and reprogramed amino acid metabolism in cancers may potentiate to mediate autophagy in protein restricted conditions (Fig.1). mTORC1 has been widely demonstrated to inhibit autophagy process by targeting the autophagy-initiating UNC-5 like autophagy activating kinase (ULK) complex, autophagy related gene 13 (ATG13), ATG13, and FIP200 [73, 74]. Meanwhile, autophagy is specifically activated in response to amino acid starvation via mTORC1 and GCN2 signaling pathways [75]. Upstream signaling study unveils that extracellular amino acid availability is sensed by the cell surface G protein coupled receptor (GPCR) TAS1R1-TAS1R3 (T1R1-T1R3), which further activates mTORC1 and inhibits autophagy [76], whereas autophagy response is markedly enhanced in fasted TAS1R3 (-/-) mice [76]. In cancer biology, autophagy has been shown to exhibit opposing and context-dependent roles in cancers, including cytoprotective, cytotoxic, nonprotective, and cytostatic form of autophagy [77]. For more specific details of autophagy and cancers, readers are referred to recent reviews [77-79] and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. Additional studies are warranted to understand the exact manner in which protein restriction in cancer treatment is govern by mTOR and autophagy. 8. Conclusion Protein restriction without malnutrition has been consistently identified as effective strategies for preventing diseases and promoting health span from yeast to human [7, 80]. In cancers, dietary protein restriction remains a negative correlation with cancer incidence, tumor growth, and mortality risk [12, 13, 20]. Introduction of low protein diets represents a novel mean to pharmacologically reprogram cellular metabolism and could emerge as an important new nutritional strategy for preventing and treating
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diseases, such as cancers. However, caution must be exercised to avoid low protein diets in old people as aging turns the beneficial effects of protein restriction on mortality into negative effects with increased cancer and overall mortality in respondents over aged 65 [13]. The reason may be explained by that low protein diets fail to provide enough amino acids and become malnourished in older subjects with lowered absorbing and metabolic abilities. Thus, Levine and colleagues suggest that protein intake should be up to 1~1.3 grams of proteins/kg of body weigh/day from 0.7~0.8 grams of proteins/kg of body weigh/day recommended by the Food and Nutrition Board of the Institute of Medicine for up to aged 65 people [13]. Although the current results are inspiring, further studies should be investigated to confirm the mechanisms of protein restriction and metabolic reprograming in cancers. For example, protein restriction is highly associated with amino acid availability and metabolism, what is the detailed relationship between protein restriction mediated-amino acid response and amino acid metabolism in specific cancer patients? Protein restriction affects the metabolism of other nutrients (i.e., lipid and carbohydrate) [81-83], while the role of lipid and carbohydrate metabolism in protein restriction-mediated cancer biology is still obscure. Indeed, a low carbohydrate/high protein diet has been reported to slow tumor growth and prevent cancer initiation [84], suggesting that protein restriction-mediated cancer treatment is highly associated with nutritional ratio, which should be further studied to uncover the precision nutrition and molecular mechanisms in cancer therapy. Both FGF21 and autophagy are in response to dietary protein restriction and involved in cancers, direct evidence should be provided in cancer models under protein limited conditions to validate the role of FGF21 and autophagy in low protein diets-mediated cancer treatment. It is clear that no single pathway accounts for all the anticancer effects of low protein diets. Besides mTOR and IGF-1 signaling pathways, is there any other signaling events or factors involving protein restriction and cancer treatment? For example, dietary protein restriction rapidly and reproducibly shapes the gut microbiota communities and increasing evidence indicate a key role of microbiome in carcinogenesis [85-87], the mediatory role of gut microbiota in protein restriction-mediated cancer treatment need to be further investigated. In the coming years, studies of protein or amino acid restriction will surely uncover more surprises and signaling mechanisms to attenuate human diseases, such as cancers, diabetes, and obesity. Authorship contributions J. Yin, W.K. Ren, X.G. Huang, T.J. Li, and Y.L. Yin discussed the topic. JY drafted the manuscript. All authors revised and approved the final manuscript. Competing interests The authors declare that they have no competing interests.
ACCEPTED MANUSCRIPT Acknowledgements We are grateful to the Public Service Technology Center, Institute of Subtropical Agriculture, Chinese Academy of Sciences for technical support. Many thanks also to the editors and reviewers for the painstaking care taken in helping improve the clarity of the manuscript. Funding
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This study was supported by the National Basic Research Program of China (973) (2013CB127301), National Natural Science Foundation of China (No. 31472106), Hunan Key Research Program (2017NK2320), and China Agriculture Research System (CARS-35).
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References
[1] M.A. Dawson, The cancer epigenome: Concepts, challenges, and therapeutic opportunities, Science 355 (2017) 1147-1152. Cancer Biology, Cell 168 (2017) 657-669.
NU
[2] M.G. Vander Heiden, R.J. DeBerardinis, Understanding the Intersections between Metabolism and [3] J.R. Mayers, M.E. Torrence, L.V. Danai, T. Papagiannakopoulos, S.M. Davidson, M.R. Bauer, A.N.
MA
Lau, B.W. Ji, P.D. Dixit, A.M. Hosios, A. Muir, C.R. Chin, E. Freinkman, T. Jacks, B.M. Wolpin, D. Vitkup, M.G. Vander Heiden, Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers, Science 353 (2016) 1161-1165. [4] A. Hattori, T. Ito, Role of Amino Acid Metabolism in Cancer Progression, Exp. Hematol. 44 (2016)
D
S78-S78.
[5] Q.H. Zhao, Y. Cao, Y. Wang, C.L. Hu, A.L. Hu, L. Ruan, Q.L. Bo, Q.F. Liu, W.J. Chen, F.B. Tao, M.
PT E
Ren, Y.S. Ge, A.G. Chen, L. Li, Plasma and tissue free amino acid profiles and their concentration correlation in patients with lung cancer, Asia. Pac. J. Clin. Nutr. 23 (2014) 429-436. [6] Y.D. Bhutia, E. Babu, S. Ramachandran, V. Ganapathy, Amino Acid Transporters in Cancer and Their Relevance to "Glutamine Addiction": Novel Targets for the Design of a New Class of Anticancer
CE
Drugs, Cancer Res. 75 (2015) 1782-1788. [7] H. Mirzaei, J.A. Suarez, V.D. Longo, Protein and amino acid restriction, aging and disease: from yeast to humans, Trends Endocrin. Met. 25 (2014) 558-566.
AC
[8] H. Mirzaei, R. Raynes, V.D. Longo, The conserved role of protein restriction in aging and disease, Curr. Opin. Clin. Nutr. 19 (2016) 74-79. [9] D. Paddon-Jones, W.W. Campbell, P.F. Jacques, S.B. Kritchevsky, L.L. Moore, N.R. Rodriguez, L.J.C. van Loon, Protein and healthy aging, Am. J. Clin. Nutr. 101 (2015) 1339s-1345s. [10] S.J. Simpson, D.G. Le Couteur, D. Raubenheimer, S.M. Solon-Biet, G.J. Cooney, V.C. Cogger, L. Fontana, Dietary protein, aging and nutritional geometry, Ageing Res. Rev. 39 (2017) 78-86. [11] L. Fontana, R.M. Adelaiye, A.L. Rastelli, K.M. Miles, E. Ciamporcero, V.D. Longo, H. Nguyen, R. Vessella, R. Pili, Dietary protein restriction inhibits tumor growth in human xenograft models of prostate and breast cancer, Oncotarget 4 (2013) 2451-2461. [12] D.W. Lamming, N.E. Cummings, A.L. Rastelli, F. Gao, E. Cava, B. Bertozzi, F. Spelta, R. Pili, L. Fontana, Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model, Oncotarget 6 (2015) 31233-31240.
ACCEPTED MANUSCRIPT [13] M.E. Levine, J.A. Suarez, S. Brandhorst, P. Balasubramanian, C.W. Cheng, F. Madia, L. Fontana, M.G. Mirisola, J. Guevara-Aguirre, J. Wan, G. Passarino, B.K. Kennedy, M. Wei, P. Cohen, E.M. Crimmins, V.D. Longo, Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population, Cell Metab. 19 (2014) 407-417. [14] E. Sanchez-Lopez, E. Flashner-Abramson, S. Shalapour, Z. Zhong, K. Taniguchi, A. Levitzki, M. Karin, Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling, Oncogene 35 (2016) 2634-2644. [15] F. Hao, Q.H. Xu, J.V. Stevens, J. Sinnett-Smith, E. Rozengurt, Crosstalk between Insulin/Igf-1 Receptor and G Protein-Coupled Receptor (Gpcr) Signaling Pathways Stimulates Yap Function in
PT
Pancreatic Ductal Adenocarcinoma Cancer (Pdac) Cells, Gastroenterology 152 (2017) S802-S802. [16] Y.F. Zhou, S.X. Li, J.T. Li, D.F. Wan, Q.X. Li, Effect of microRNA-135a on Cell Proliferation,
RI
Migration, Invasion, Apoptosis and Tumor Angiogenesis Through the IGF-1/PI3K/Akt Signaling Pathway in Non-Small Cell Lung Cancer, Cell. Physiol. Biochem. 42 (2017) 1431-1446.
SC
[17] P.F. Christopoulos, A. Corthay, M. Koutsilieris, Aiming for the Insulin-like Growth Factor-1 system in breast cancer therapeutics, Cancer Treat. Rev. 63 (2017) 79-95. [18] W. Cai, M. Sakaguchi, A. Kleinridders, G. Gonzalez-Del Pino, J.M. Dreyfuss, B.T. O'Neill, A.K.
NU
Ramirez, H. Pan, J.N. Winnay, J. Boucher, M.J. Eck, C.R. Kahn, Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression, Nat. Commun. 8 (2017) 14892. [19] R.C. Travis, P.N. Appleby, R.M. Martin, J.M.P. Holly, D. Albanes, A. Black, H.B.
MA
Bueno-de-Mesquita, J.M. Chan, C. Chen, M.D. Chirlaque, M.B. Cook, M. Deschasaux, J.L. Donovan, L. Ferrucci, P. Galan, G.G. Giles, E.L. Giovannucci, M.J. Gunter, L.A. Habel, F.C. Hamdy, K.J. Helzlsouer, S. Hercberg, R.N. Hoover, J.A.M.J.L. Janssen, R. Kaaks, T. Kubo, L. Le Marchand, E.J. Metter, K. Mikami, J.K. Morris, D.E. Neal, M.L. Neuhouser, K. Ozasa, D. Palli, E.A. Platz, M.N.
D
Pollak, A.J. Price, M.J. Roobol, C. Schaefer, J.M. Schenk, G. Severi, M.J. Stampfer, P. Stattin, A. Tamakoshi, C.M. Tangen, M. Touvier, N.J. Wald, N.S. Weiss, R.G. Ziegler, T.J. Key, N.E. Allen, E.H.
PT E
Nutr, A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk, Cancer Res. 76 (2016) 2288-2300. [20] L. Fontana, S. Klein, J.O. Holloszy, Long-term low-protein, low-calorie diet and endurance 1456-1462.
CE
exercise modulate metabolic factors associated with cancer risk, Am. J. Clin. Nutr. 84 (2006) [21] E. Eitan, V. Tosti, C.N. Suire, E. Cava, S. Berkowitz, B. Bertozzi, S.M. Raefsky, N. Veronese, R. Spangler, F. Spelta, M. Mustapic, D. Kapogiannis, M.P. Mattson, L. Fontana, In a randomized trial in
AC
prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles, Aging Cell 16 (2017) 1430-1433. [22] C.H. Lee, F.M. Safdie, L. Raffaghello, M. Wei, F. Madia, E. Parrella, D. Hwang, P. Cohen, G. Bianchi, V.D. Longo, Reduced Levels of IGF-I Mediate Differential Protection of Normal and Cancer Cells in Response to Fasting and Improve Chemotherapeutic Index, Cancer Res. 70 (2010) 1564-1572. [23] S. Brandhorst, M. Wei, S. Hwang, T.E. Morgan, V.D. Longo, Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression, Exp. Gerontol. 48 (2013) 1120-1128. [24] P.F. Christopoulos, P. Msaouel, M. Koutsilieris, The role of the insulin-like growth factor-1 system in breast cancer, Mol. Cancer 14 (2015) 43. [25] H. Li, I.S. Batth, X. Qu, L. Xu, N. Song, R. Wang, Y. Liu, IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: overview and new insights, Mol. Cancer 16
ACCEPTED MANUSCRIPT (2017) 6. [26] O. Meynet, J.E. Ricci, Caloric restriction and cancer: molecular mechanisms and clinical implications, Trends Mol. Med. 20 (2014) 419-427. [27] J. Standard, Y. Jiang, M. Yu, X.Y. Su, Z.H. Zhao, J.T. Xu, J. Chen, B. King, L.Z. Lu, J. Tomich, R. Baybutt, W.Q. Wang, Reduced signaling of PI3K-Akt and RAS-MAPK pathways is the key target for weight-loss-induced cancer prevention by dietary calorie restriction and/or physical activity, J. Nutr. Biochem. 25 (2014) 1317-1323. [28] J. Yin, Y. Li, X. Zhu, H. Han, W. Ren, S. Chen, P. Bin, G. Liu, X. Huang, R. Fang, B. Wang, K. Wang, L. Sun, T. Li, Y. Yin, Effects of Long-Term Protein Restriction on Meat Quality, Muscle Amino
PT
Acids, and Amino Acid Transporters in Pigs, J. Agric. Food Chem. 65 (2017) 9297-9304. [29] T. Barnes, K. Bell, K.M. DiSebastiano, V. Vance, R. Hanning, C. Russell, J.A. Dubin, M. Bahl, N.
RI
Califaretti, C. Campbell, M. Mourtzakis, Plasma amino acid profiles of breast cancer patients early in the trajectory of the disease differ from healthy comparison groups, Appl. Physiol. Nutr. Metab. 39
SC
(2014) 740-744.
[30] A. Hasim, A. Aili, A. Maimaiti, B. Mamtimin, A. Abudula, H. Upur, Plasma-free amino acid profiling of cervical cancer and cervical intraepithelial neoplasia patients and its application for early
NU
detection, Mol. Biol. Rep. 40 (2013) 5853-5859.
[31] B.J. Altman, Z.E. Stine, C.V. Dang, From Krebs to clinic: glutamine metabolism to cancer therapy (vol 16, pg 619, 2016), Nat. Rev. Cancer 16 (2016) 773-773.
MA
[32] W.J. Huang, W. Choi, Y.L. Chen, Q. Zhang, H.T. Deng, W. He, Y.G. Shi, A proposed role for glutamine in cancer cell growth through acid resistance, Cell Res. 23 (2013) 724-727. [33] A. Ribas, Adaptive Immune Resistance: How Cancer Protects from Immune Attack, Cancer Discov. 5 (2015) 915-919.
D
[34] F. Marcucci, C. Rumio, A. Corti, Tumor cell-associated immune checkpoint molecules – Drivers of malignancy and stemness, BBA-Rev. Cancer 1868 (2017) 571-583.
PT E
[35] Y. He, M. Gao, Y. Cao, H. Tang, S. Liu, Y. Tao, Nuclear localization of metabolic enzymes in immunity and metastasis, BBA-Rev. Cancer 1868 (2017) 359-371. [36] C. Corbet, O. Feron, Cancer cell metabolism and mitochondria: Nutrient plasticity for TCA cycle fueling, BBA-Rev. Cancer 1868 (2017) 7-15.
CE
[37] M. Nakaya, Y. Xiao, X. Zhou, J.H. Chang, M. Chang, X. Cheng, M. Blonska, X. Lin, S.C. Sun, Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation, Immunity 40 (2014) 692-705.
AC
[38] L.V. Sinclair, J. Rolf, E. Emslie, Y.B. Shi, P.M. Taylor, D.A. Cantrell, Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation, Nat. Immunol. 14 (2013) 500-508. [39] E.H. Ma, G. Bantug, T. Griss, S. Condotta, R.M. Johnson, B. Samborska, N. Mainolfi, V. Suri, H. Guak, M.L. Balmer, M.J. Verway, T.C. Raissi, H. Tsui, G. Boukhaled, S. Henriques da Costa, C. Frezza, C.M. Krawczyk, A. Friedman, M. Manfredi, M.J. Richer, C. Hess, R.G. Jones, Serine Is an Essential Metabolite for Effector T Cell Expansion, Cell Metab. 25 (2017) 345-357. [40] J. Godin-Ethier, L.A. Hanafi, C.A. Piccirillo, R. Lapointe, Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic Perspectives, Clin. Cancer Res. 17 (2011) 6985-6991. [41] A. Amobi, F. Qian, A.A. Lugade, K. Odunsi, Tryptophan Catabolism and Cancer Immunotherapy Targeting IDO Mediated Immune Suppression, Adv. Exp. Med. Biol. 1036 (2017) 129-144.
ACCEPTED MANUSCRIPT [42] R. Geiger, J.C. Rieckmann, T. Wolf, C. Basso, Y. Feng, T. Fuhrer, M. Kogadeeva, P. Picotti, F. Meissner, M. Mann, N. Zamboni, F. Sallusto, A. Lanzavecchia, L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity, Cell 167 (2016) 829-842 e813. [43] G.M. Tannahill, A.M. Curtis, J. Adamik, E.M. Palsson-McDermott, A.F. McGettrick, G. Goel, C. Frezza, N.J. Bernard, B. Kelly, N.H. Foley, L. Zheng, A. Gardet, Z. Tong, S.S. Jany, S.C. Corr, M. Haneklaus, B.E. Caffrey, K. Pierce, S. Walmsley, F.C. Beasley, E. Cummins, V. Nizet, M. Whyte, C.T. Taylor, H. Lin, S.L. Masters, E. Gottlieb, V.P. Kelly, C. Clish, P.E. Auron, R.J. Xavier, L.A. O'Neill, Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha, Nature 496 (2013) 238-242.
PT
[44] P.S. Liu, H. Wang, X. Li, T. Chao, T. Teav, S. Christen, G. Di Conza, W.C. Cheng, C.H. Chou, M. Vavakova, C. Muret, K. Debackere, M. Mazzone, H.D. Huang, S.M. Fendt, J. Ivanisevic,
RI
α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming, Nat. Immunol. 18 (2017) 985-994.
SC
[45] A.K. Sikalidis, Amino Acids and Immune Response: A Role for Cysteine, Glutamine, Phenylalanine, Tryptophan and Arginine in T-cell Function and Cancer?, Pathol. Oncol. Res. 21 (2015) 9-17.
NU
[46] R.A. Saxton, D.M. Sabatini, mTOR Signaling in Growth, Metabolism, and Disease, Cell 168 (2017) 960-976.
[47] O. Leavy, NLRC3 inhibits mTOR in colorectal cancer, Nat. Rev. Immunol. 17 (2017) 79-79.
MA
[48] Y.Q. Zhang, P.K.S. Ng, M. Kucherlapati, F.J. Chen, Y.X. Liu, Y.H. Tsang, G. de Velasco, K.J. Jeong, R. Akbani, A. Hadjipanayis, A. Pantazi, C.A. Bristow, E. Lee, H.S. Mahadeshwar, J.B. Tang, J.H. Zhang, L.X. Yang, S. Seth, S. Lee, X.J. Ren, X.Z. Song, H.D. Sun, J. Seidman, L.J. Luquette, R.B. Xi, L. Chin, A. Protopopov, T.F. Westbrook, C.S. Shelley, T.K. Choueiri, M. Ittmann, C. Van Waes, J.N.
D
Weinstein, H. Liang, E.P. Henske, A.K. Godwin, P.J. Park, R. Kucherlapati, K.L. Scott, G.B. Mills, D.J. Kwiatkowski, C.J. Creighton, A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway
PT E
Alterations, Cancer Cell 31 (2017) 820-+.
[49] J. Polivka, Jr., F. Janku, Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway, Pharmacol. Ther. 142 (2014) 164-175.
[50] M.T. Lau, P.C. Leung, The PI3K/Akt/mTOR signaling pathway mediates insulin-like growth
CE
factor 1-induced E-cadherin down-regulation and cell proliferation in ovarian cancer cells, Cancer Lett. 326 (2012) 191-198.
[51] M. Molina-Arcas, D.C. Hancock, C. Sheridan, M.S. Kumar, J. Downward, Coordinate Direct
AC
Input of Both KRAS and IGF1 Receptor to Activation of PI3 Kinase in KRAS-Mutant Lung Cancer, Cancer Discov. 3 (2013) 548-563. [52] I.A. Mayer, C.L. Arteaga, The PI3K/AKT Pathway as a Target for Cancer Treatment, Annu. Rev. Med. 67 (2016) 11-28. [53] S. Ebrahimi, M. Hosseini, S. Shahidsales, M. Maftouh, G.A. Ferns, M. Ghayour-Mobarhan, S.M. Hassanian, A. Avan, Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer, Curr. Med. Chem. 24 (2017) 1321-1331. [54] F. Chiarini, C. Evangelisti, J.A. McCubrey, A.M. Martelli, Current treatment strategies for inhibiting mTOR in cancer, Trends Pharmacol. Sci. 36 (2015) 124-135. [55] A.Y. Minard, S.X. Tan, P.Y. Yang, D.J. Fazakerley, W. Domanova, B.L. Parker, S.J. Humphrey, R. Jothi, J. Stockli, D.E. James, mTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes, Cell Rep. 17 (2016) 29-36.
ACCEPTED MANUSCRIPT [56] T. Laeger, D.C. Albarado, S.J. Burke, L. Trosclair, J.W. Hedgepeth, H.R. Berthoud, T.W. Gettys, J.J. Collier, H. Munzberg, C.D. Morrison, Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2, Cell Rep. 16 (2016) 707-716. [57] C.M. Hill, T. Laeger, D.C. Albarado, D.H. McDougal, H.R. Berthoud, H. Munzberg, C.D. Morrison, Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints, Sci. Rep. 7 (2017) 8209. [58] T. Laeger, T.M. Henagan, D.C. Albarado, L.M. Redman, G.A. Bray, R.C. Noland, H. Munzberg, S.M. Hutson, T.W. Gettys, M.W. Schwartz, C.D. Morrison, FGF21 is an endocrine signal of protein restriction, J. Clin. Invest. 124 (2014) 3913-3922.
PT
[59] K. Stemmer, F. Zani, K.M. Habegger, C. Neff, P. Kotzbeck, M. Bauer, S. Yalamanchilli, A. Azad, M. Lehti, P.J. Martins, T.D. Muller, P.T. Pfluger, R.J. Seeley, FGF21 is not required for glucose
RI
homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice, Diabetologia 58 (2015) 2414-2423.
SC
[60] T. Laeger, C. Baumeier, I. Wilhelmi, J. Wurfel, A. Kamitz, A. Schurmann, FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes, Diabetologia 60 (2017) 2274-2284.
NU
[61] T. Chalvon-Demersay, P.C. Even, D. Tome, C. Chaumontet, J. Piedcoq, C. Gaudichon, D. Azzout-Marniche, Low-protein diet induces, whereas high-protein diet reduces hepatic FGF21 production in mice, but glucose and not amino acids up-regulate FGF21 in cultured hepatocytes, J. Nutr.
MA
Biochem. 36 (2016) 60-67.
[62] M.J. Potthoff, Fgf21 and Metabolic Disease in 2016 a New Frontier in Fgf21 Biology, Nat. Rev. Endocrinol. 13 (2017) 74-76.
[63] M.E. Knott, J.N. Minatta, L. Roulet, G. Gueglio, L. Pasik, S.M. Ranuncolo, M. Nunez, L. Puricelli,
D
M.S. De Lorenzo, Circulating Fibroblast Growth Factor 21 (Fgf21) as Diagnostic and Prognostic Biomarker in Renal Cancer, J. Mol. Biomark. Diagn. 1 (2016) Suppl 2.
PT E
[64] Q. Zhang, Y. Li, T. Liang, X. Lu, X. Liu, C. Zhang, X. Jiang, R.C. Martin, M. Cheng, L. Cai, Loss of FGF21 in diabetic mouse during hepatocellular carcinogenetic transformation, Am. J. Cancer Res. 5 (2015) 1762-1774.
[65] X. Huang, C. Yu, C. Jin, C. Yang, R. Xie, D. Cao, F. Wang, W.L. McKeehan, Forced expression of fibroblast
CE
hepatocyte-specific
growth
factor
21
delays
initiation
of
chemically
induced
hepatocarcinogenesis, Mol. Carcinog. 45 (2006) 934-942. [66] P. Xu, Y. Zhang, W. Wang, Q. Yuan, Z. Liu, L.M. Rasoul, Q. Wu, M. Liu, X. Ye, D. Li, G. Ren,
AC
Long-Term Administration of Fibroblast Growth Factor 21 Prevents Chemically-Induced Hepatocarcinogenesis in Mice, Dig. Dis. Sci. 60 (2015) 3032-3043. [67] S. Kralisch, A. Tonjes, K. Krause, J. Richter, U. Lossner, P. Kovacs, T. Ebert, M. Bluher, M. Stumvoll, M. Fasshauer, Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans, J. Endocrinol. 216 (2013) 135-143. [68] Y. Zhang, Y. Xie, E.D. Berglund, K.C. Coate, T.T. He, T. Katafuchi, G. Xiao, M.J. Potthoff, W. Wei, Y. Wan, R.T. Yu, R.M. Evans, S.A. Kliewer, D.J. Mangelsdorf, The starvation hormone, fibroblast growth factor-21, extends lifespan in mice, Elife 1 (2012) e00065. [69] T. Inagaki, V.Y. Lin, R. Goetz, M. Mohammadi, D.J. Mangelsdorf, S.A. Kliewer, Inhibition of growth hormone signaling by the fasting-induced hormone FGF21, Cell Metab. 8 (2008) 77-83. [70] M. Kitada, Y. Ogura, T. Suzuki, S. Sen, S.M. Lee, K. Kanasaki, S. Kume, D. Koya, A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by
ACCEPTED MANUSCRIPT suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity, Diabetologia 59 (2016) 1307-1317. [71] H. Wang, G.J. Wilson, D. Zhou, S. Lezmi, X.W. Chen, D.K. Layman, Y.X. Pan, Induction of autophagy through the activating transcription factor 4 (ATF4)-dependent amino acid response pathway in maternal skeletal muscle may function as the molecular memory in response to gestational protein restriction to alert offspring to maternal nutrition, Brit. J. Nutr. 114 (2015) 519-532. [72] T.M. Henagan, T. Laeger, A.M. Navard, D. Albarado, R.C. Noland, K. Stadler, C.M. Elks, D. Burk, C.D. Morrison, Hepatic autophagy contributes to the metabolic response to dietary protein restriction, Metabolism 65 (2016) 805-815.
PT
[73] Z. Li, Y. Song, L. Liu, N. Hou, X. An, D. Zhan, Y. Li, L. Zhou, P. Li, L. Yu, J. Xia, Y. Zhang, J. Wang, X. Yang, miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR
RI
activation, Cell Death. Differ. 24 (2017) 1205-1213.
[74] S. Ruf, A.M. Heberle, M. Langelaar-Makkinje, S. Gelino, D. Wilkinson, C. Gerbeth, J.J. Schwarz,
SC
B. Holzwarth, B. Warscheid, C. Meisinger, M.A.T.M. van Vugt, R. Baumeister, M. Hansen, K. Thedieck, PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy, Autophagy 13 (2017) 486-505.
NU
[75] B. Carroll, V.I. Korolchuk, S. Sarkar, Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis, Amino Acids 47 (2015) 2065-2088. [76] E.M. Wauson, E. Zaganjor, M.H. Cobb, Amino acid regulation of autophagy through the GPCR
MA
TAS1R1-TAS1R3, Autophagy 9 (2013) 418-419.
[77] D.A. Gewirtz, The four faces of autophagy: implications for cancer therapy, Cancer Res. 74 (2014) 647-651.
[78] J.M.M. Levy, C.G. Towers, A. Thorburn, Targeting autophagy in cancer, Nat. Rev. Cancer 17
D
(2017) 528-542.
[79] E. White, The role for autophagy in cancer, J. Clin. Invest. 125 (2015) 42-46.
PT E
[80] H. Mirzaei, R. Raynes, V.D. Longo, The conserved role of protein restriction in aging and disease, Curr. Opin. Clin. Nutr. Metab. Care 19 (2016) 74-79. [81] A.P. Martins, P.A. Lopes, M.S. Madeira, S.V. Martins, N.C. Santos, T.F. Moura, J.A. Prates, G. Soveral, Differences in lipid deposition and adipose membrane biophysical properties from lean and
CE
obese pigs under dietary protein restriction, Biochem. Biophys. Res. Commun. 423 (2012) 170-175. [82] S.M. Solon-Biet, S.J. Mitchell, S.C. Coogan, V.C. Cogger, R. Gokarn, A.C. McMahon, D. Raubenheimer, R. de Cabo, S.J. Simpson, D.G. Le Couteur, Dietary Protein to Carbohydrate Ratio and
AC
Caloric Restriction: Comparing Metabolic Outcomes in Mice, Cell Rep. 11 (2015) 1529-1534. [83] L. Zitvogel, F. Pietrocola, G. Kroemer, Nutrition, inflammation and cancer, Nat. Immunol. 18 (2017) 843-850.
[84] V.W. Ho, K. Leung, A. Hsu, B. Luk, J. Lai, S.Y. Shen, A.I. Minchinton, D. Waterhouse, M.B. Bally, W. Lin, B.H. Nelson, L.M. Sly, G. Krystal, A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation, Cancer Res. 71 (2011) 4484-4493. [85] W.S. Garrett, Cancer and the microbiota, Science 348 (2015) 80-86. [86] L. Zitvogel, M. Ayyoub, B. Routy, G. Kroemer, Microbiome and Anticancer Immunosurveillance, Cell 165 (2016) 276-287. [87] T.A. Scott, L.M. Quintaneiro, P. Norvaisas, P.P. Lui, M.P. Wilson, K.Y. Leung, L. Herrera-Dominguez, S. Sudiwala, A. Pessia, P.T. Clayton, K. Bryson, V. Velagapudi, P.B. Mills, A. Typas, N.D.E. Greene, F. Cabreiro, Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C.
ACCEPTED MANUSCRIPT elegans, Cell 169 (2017) 442-456 e418. [88] A.M. Proenza, J. Oliver, A. Palou, P. Roca, Breast and lung cancer are associated with a decrease in blood cell amino acid content, J. Nutr. Biochem. 14 (2003) 133-138. [89] M. Shingyoji, T. Iizasa, M. Higashiyama, F. Imamura, N. Saruki, A. Imaizumi, H. Yamamoto, T. Daimon, O. Tochikubo, T. Mitsushima, M. Yamakado, H. Kimura, The significance and robustness of a plasma free amino acid (PFAA) profile-based multiplex function for detecting lung cancer, BMC cancer 13 (2013) 77. [90] Y. Miyagi, M. Higashiyama, A. Gochi, M. Akaike, T. Ishikawa, T. Miura, N. Saruki, E. Bando, H. Kimura, F. Imamura, M. Moriyama, I. Ikeda, A. Chiba, F. Oshita, A. Imaizumi, H. Yamamoto, H.
PT
Miyano, K. Horimoto, O. Tochikubo, T. Mitsushima, M. Yamakado, N. Okamoto, Plasma free amino acid profiling of five types of cancer patients and its application for early detection, PLoS One 6 (2011)
RI
e24143.
[91] H.J. Kim, S.H. Jang, J.S. Ryu, J.E. Lee, Y.C. Kim, M.K. Lee, T.W. Jang, S.Y. Lee, H. Nakamura,
SC
N. Nishikata, M. Mori, Y. Noguchi, H. Miyano, K.Y. Lee, The performance of a novel amino acid multivariate index for detecting lung cancer: A case control study in Korea, Lung Cancer 90 (2015) 522-527.
NU
[92] A. Klupczynska, P. Derezinski, W. Dyszkiewicz, K. Pawlak, M. Kasprzyk, Z.J. Kokot, Evaluation of serum amino acid profiles' utility in non-small cell lung cancer detection in Polish population, Lung Cancer 100 (2016) 71-76.
MA
[93] Y. Gu, T.X. Chen, S.Z. Fu, X. Sun, L.Y. Wang, J. Wang, Y.F. Lu, S.M. Ding, G.D. Ruan, L.S. Teng, M. Wang, Perioperative dynamics and significance of amino acid profiles in patients with cancer, J. Transl. Med. 13 (2015).
[94] P. Derezinski, A. Klupczynska, W. Sawicki, J.A. Palka, Z.J. Kokot, Amino Acid Profiles of Serum
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and Urine in Search for Prostate Cancer Biomarkers: a Pilot Study, Int. J. Med. Sci. 14 (2017) 1-12.
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Figure legends Fig.1 Working model of protein restriction in cancers. Five pathways are mainly involved in the mechanism of protein restriction in cancers, including FGF21, IGF-1, mTOR, amino acid reprograming, and autophagy. Abbreviations: AA, amino acids; PI3K, phosphoinositide 3-kinase; GCN2, general control nonderepressible 2; UCPs, uncoupling proteins; FGF21, fibroblast growth factor 21; Akt, protein kinase B; IGF-1R, insulin-like growth factor 1 receptor; IGF-1, insulin-like growth factor 1; mTOR, mammalian target of rapamycin.
ACCEPTED MANUSCRIPT Table 1 Amino acid changes in cancer patients. Abbreviations: AA, amino acids; NSCLC, non-small cell lung cancer; Glu, glutamate; Asp, aspartate; Cys, cysteine; Cit, Citrulline; Orn, ornithine; Ala, alanine (Ala); Arg, arginine; Asn, asparagine; Gln, glutamine; Gly, glycine; His, histidine; Ile, isoleucine; Leu, leucine; Lys, lysine; Met, methionine; Phe, phenylalanine; Pro, proline; Ser, serine; Thr, threonine; Trp, tryptophan; Tyr, tyrosine (Tyr); Val, valine. Country
Cases
Increased AA
Decreased AA
Ref
Lung cancer
China
27
Blood: Phe
Blood: Trp, Gly, Cit, Orn, and Pro
[5]
Cancer tissue: Tau,
Cancer tissue: Lys and Orn
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Cancer type
Glu, and Gly Spain
14
Lung Cancer
Japan
171
Blood: Val and Pro
[88]
Blood: Pro, Val, Ile,
Blood: Asn, Gln, Ala, Cit, Met, His, and
[89]
Leu, Tyr, Phe, and
Trp,
Lung cancer
Japan
200
Blood:
Ser,
Pro,
Gly, Met, Ile, Leu,
Lung cancer
Korean
Blood: Asn, Gln, Cit, His, Trp, and Orn
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and Phe
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Orn,
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Lung cancer
75
Blood: Thr, Asn, Gln, Gly, Ala, Cit, Val,
[90]
[91]
Met, Leu, His, Trp, Lys, and Arg
Poland
90
patients
Blood: β-Ala and Phe
China
199
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Gastric cancer
Japan
Blood:
Thr,
Cys,
and Arg
Colorectal
Japan
[92]
Blood: Thr, Asn, Gln, Ala, Cit, Val,
[90]
Met, Ile, Leu, Tyr, Phe, His, Trp, Lys,
Blood: Asp, Ser, Glu, Gly, Ala, Val,
[93]
Lys, His, and Pro
199
Blood: Thr, Asn, Gln, Cit, Val, Met,
[90]
Leu, Tyr, Phe, His, Trp, Orn, Lys, and Arg
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cancer
Blood: Ala, Arg, Asp, Cit, Pro, and Ser
and Arg
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Gastric cancer
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NSCLC
Blood:
Breast cancer
China
28
Blood: Thr and Arg
Breast cancer
Spain
16
Breast cancer
Canada
8
Blood: Glu and His
Blood: Thr
[29]
Thyroid cancer
China
33
Blood:
Blood: Asp, Glu, Gly, and Pro
[93]
Blood: Asp, Glu, Ser, Gly, His, Tau,
[30]
Japan
AC
Breast cancer
196
Thr,
Ser,
Blood: Gln, Pro, Tyr, Phe, His, and Trp
[90]
Blood: Asp, Glu, and Gly,
[93]
Blood: Asp and Glu
[88]
Gly, Ala, Orn, and Lys
Thr,
Met,
Leu, Tyr, Lys, and Arg Cervical
China
26
Blood: Arg and Thr
intraepithelial
Ala, Pro, Tyr, Val, Met, Lys, Ile, Leu,
neoplasia
and Phe,
Prostate cancer
Poland
49
Blood: Arg, Asp,
Blood: Ala, Glu, Gln, His, Ile, Leu, Lys,
and β-Ala
Met, and Phe,
Urine: Tau
Urine: Arg, Cit, Cys, Glu, Gln, His, Ile,
[94 ]
ACCEPTED MANUSCRIPT Leu, Lys, Met, Orn, Phe, Ser, Trp, and Tyr Prostate cancer
Japan
134
Blood:
Ala,
Orn,
Blood: Gln, Val, Leu, Trp, and Arg
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and Lys
[90]
Figure 1