- Email: [email protected]
Feasibility of ketogenic diet to treat renal cell carcinoma in vivo
e116
Abstracts
potential of cancer cells by inducing reactive oxygen species and hypoxiainducible factor-1a (HIF1a) stabilization. Conversely, our group described the loss of respiratory Complex I (CI) in low-proliferative oncocytic tumors, where the metabolic rearrangements that follow CI disassembly were shown to induce HIF1a degradation, inhibiting the adaptation to hypoxia [1]. We hence hypothesized that, whereas mild mitochondrial impairment may sustain tumorigenesis, a severe CI dysfunction would induce chronic HIF1a destabilization, preventing progression to malignancy. To this aim, CI deficient cell models were generated to induce the knock-out of NDUFS3 (NDUFS3 KO), which encodes an essential CI assembly subunit. The biochemical characterization revealed a strong decrease of CI activity leading to a severe mitochondrial impairment in NDUFS3 KO clones. Metabolomic analysis showed a marked difference in Krebs cycle metabolite levels between NDUFS3 KO and wild-type clones, in particular an increase of αKG/SA ratio in NDUFS3 KOs. This was followed by a decreased amount of stabilized HIF1a protein and a lower expression of HIF1a responsive genes in NDUFS3 KO clones, without affecting HIF1A gene expression. Experiments in immunodeficient mice showed that the lack of CI prevents xenografts growth. References 1. Calabrese C, Iommarini L, Kurelac I, Calvaruso MA, Capristo M, Lollini PL, Nanni P, Bergamini C, Nicoletti G, Giovanni CD, Ghelli A, Giorgio V, Caratozzolo MF, Marzano F, Manzari C, Betts CM, Carelli V, Ceccarelli C, Attimonelli M, Romeo G, Fato R, Rugolo M, Tullo A, Gasparre G, Porcelli AM, Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells, Cancer Metab (2013) 1:11.
(different triglyceride mixtures; fat 78%, protein 8%, carbohydrates 1%). KD intervention was able to reduce tumor growth. KD increased the levels of ketone bodies in the blood in the first days of treatment only, whereas blood glucose levels remained unaffected. Strikingly, the survival of mice under KD was reduced due to a massive and sudden weight loss, greater than 20% of the initial mouse body weight. RCC often presents non-metastatic hepatic dysfunction in humans. Hepatic dysfunction could be the reason why mice could not metabolize the high triglyceride content of KD and developed liver steatosis. Our preliminary data suggest that metabolically targeting RCC with KD might not be feasible, due to possible liver toxicity. References 1. D. Meierhofer, J. A. Mayr, U. Foetschl, A. Berger, K. Fink, N. Schmeller, G.W. Hacker, C. Hauser-Kronberger, B. Kofler, W. Sperl, Decrease of mitochondrial DNA content and energy metabolism in renal cell carcinoma, Carcinogenesis 25(6) (2004) 1005–1010 2. R. J. Morscher, S. Aminzadeh-Gohari, R. G. Feichtinger, J. A. Mayr, R. Lang, D. Neureiter, W. Sperl, B. Kofler, Inhibition of neuroblastoma tumor growth by ketogenic diet and/or calorie restriction in a CD1Nu mouse model, PLoS One 10(6) (2015) e0129802. doi:10.1016/j.bbabio.2016.04.348
11.21.
doi:10.1016/j.bbabio.2016.04.347 Fatty acid synthase inhibition: Metabolic reprogramming leading to cancer cell death Nastasia Wilfinger, Kristina Kührer, Magdalena Billerhart, Karin Nowikovsky 11.20. Feasibility of ketogenic diet to treat renal cell carcinoma in vivo Silvia Vidalia,, Sepideh Aminzadeh-Goharia, René G. Feichtingera, Renaud Vatrinetb,c, Felix Lockera, Tricia Rutherfordd, Maura O’Donneld, Andrea Stöger-Kleiberd, Wolfgang Sperle, Anna Maria Porcellib, Barbara Koflera a
Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria b Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy c Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy d Clinical Nutrition Vitaflo International, Liverpool, UK e Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria E-mail address: [email protected] (S. Vidali) Renal cell carcinoma (RCC), the most common kidney cancer in adults, is characterized by a reduction of the complexes of the respiratory chain and a metabolic shift to aerobic glycolysis [1]. Recently, it was shown that neuroblastoma, a tumor with a similar metabolic signature, can be targeted by ketogenic diet (KD), which is high in fat and low in glucose and protein [2]. Our aim was to test the feasibility of KD to treat RCC in a murine xenograft model. Human RCC xenografts were established in CD1 nu/nu mice. Mice were randomized to a control diet group or 3 KD treatment groups
Department of Internal Medicine I, Medical University Vienna, Vienna, Austria E-mail address: nastasia.wilfi[email protected] (N. Wilfinger) A wide range of cancer types relies on de novo lipid synthesis to meet the high demand for membrane formation during rapid proliferation and thereby predominantly activates the fatty acid synthase (FASN). Thus, FASN has become an attractive target of antineoplastic therapies. So far, most of the newly developed drugs inhibiting the lipid metabolism showed side toxicities or low solubility. Testing a novel promising epigallocatechin-3-gallate based compound, we found that it induced a metabolic switch from oxidative phosphorylation to glycolysis and ultimately induced glucose-dependent cell death in ovarian cancer cells. The cytotoxic effect of FASN inhibition was accompanied by a strong upregulation of HIF-1alpha and its downstream target REDD-1, a protein with a critical role in inhibiting mTOR during hypoxia. Intrigued by the fact that general hallmarks of cancer survival and aggressiveness like hypoxia and glycolysis were connected with cell death, we extended our study to better understand the metabolic mechanism leading to cell death. We present data on drastic metabolic alterations which included citrate, α-ketoglutarate and succinate and were induced by genetic or biochemical inhibition of FASN, revealing a novel powerful anticancer strategy. doi:10.1016/j.bbabio.2016.04.349
Abstracts
potential of cancer cells by inducing reactive oxygen species and hypoxiainducible factor-1a (HIF1a) stabilization. Conversely, our group described the loss of respiratory Complex I (CI) in low-proliferative oncocytic tumors, where the metabolic rearrangements that follow CI disassembly were shown to induce HIF1a degradation, inhibiting the adaptation to hypoxia [1]. We hence hypothesized that, whereas mild mitochondrial impairment may sustain tumorigenesis, a severe CI dysfunction would induce chronic HIF1a destabilization, preventing progression to malignancy. To this aim, CI deficient cell models were generated to induce the knock-out of NDUFS3 (NDUFS3 KO), which encodes an essential CI assembly subunit. The biochemical characterization revealed a strong decrease of CI activity leading to a severe mitochondrial impairment in NDUFS3 KO clones. Metabolomic analysis showed a marked difference in Krebs cycle metabolite levels between NDUFS3 KO and wild-type clones, in particular an increase of αKG/SA ratio in NDUFS3 KOs. This was followed by a decreased amount of stabilized HIF1a protein and a lower expression of HIF1a responsive genes in NDUFS3 KO clones, without affecting HIF1A gene expression. Experiments in immunodeficient mice showed that the lack of CI prevents xenografts growth. References 1. Calabrese C, Iommarini L, Kurelac I, Calvaruso MA, Capristo M, Lollini PL, Nanni P, Bergamini C, Nicoletti G, Giovanni CD, Ghelli A, Giorgio V, Caratozzolo MF, Marzano F, Manzari C, Betts CM, Carelli V, Ceccarelli C, Attimonelli M, Romeo G, Fato R, Rugolo M, Tullo A, Gasparre G, Porcelli AM, Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells, Cancer Metab (2013) 1:11.
(different triglyceride mixtures; fat 78%, protein 8%, carbohydrates 1%). KD intervention was able to reduce tumor growth. KD increased the levels of ketone bodies in the blood in the first days of treatment only, whereas blood glucose levels remained unaffected. Strikingly, the survival of mice under KD was reduced due to a massive and sudden weight loss, greater than 20% of the initial mouse body weight. RCC often presents non-metastatic hepatic dysfunction in humans. Hepatic dysfunction could be the reason why mice could not metabolize the high triglyceride content of KD and developed liver steatosis. Our preliminary data suggest that metabolically targeting RCC with KD might not be feasible, due to possible liver toxicity. References 1. D. Meierhofer, J. A. Mayr, U. Foetschl, A. Berger, K. Fink, N. Schmeller, G.W. Hacker, C. Hauser-Kronberger, B. Kofler, W. Sperl, Decrease of mitochondrial DNA content and energy metabolism in renal cell carcinoma, Carcinogenesis 25(6) (2004) 1005–1010 2. R. J. Morscher, S. Aminzadeh-Gohari, R. G. Feichtinger, J. A. Mayr, R. Lang, D. Neureiter, W. Sperl, B. Kofler, Inhibition of neuroblastoma tumor growth by ketogenic diet and/or calorie restriction in a CD1Nu mouse model, PLoS One 10(6) (2015) e0129802. doi:10.1016/j.bbabio.2016.04.348
11.21.
doi:10.1016/j.bbabio.2016.04.347 Fatty acid synthase inhibition: Metabolic reprogramming leading to cancer cell death Nastasia Wilfinger, Kristina Kührer, Magdalena Billerhart, Karin Nowikovsky 11.20. Feasibility of ketogenic diet to treat renal cell carcinoma in vivo Silvia Vidalia,, Sepideh Aminzadeh-Goharia, René G. Feichtingera, Renaud Vatrinetb,c, Felix Lockera, Tricia Rutherfordd, Maura O’Donneld, Andrea Stöger-Kleiberd, Wolfgang Sperle, Anna Maria Porcellib, Barbara Koflera a
Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria b Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy c Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy d Clinical Nutrition Vitaflo International, Liverpool, UK e Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria E-mail address: [email protected] (S. Vidali) Renal cell carcinoma (RCC), the most common kidney cancer in adults, is characterized by a reduction of the complexes of the respiratory chain and a metabolic shift to aerobic glycolysis [1]. Recently, it was shown that neuroblastoma, a tumor with a similar metabolic signature, can be targeted by ketogenic diet (KD), which is high in fat and low in glucose and protein [2]. Our aim was to test the feasibility of KD to treat RCC in a murine xenograft model. Human RCC xenografts were established in CD1 nu/nu mice. Mice were randomized to a control diet group or 3 KD treatment groups
Department of Internal Medicine I, Medical University Vienna, Vienna, Austria E-mail address: nastasia.wilfi[email protected] (N. Wilfinger) A wide range of cancer types relies on de novo lipid synthesis to meet the high demand for membrane formation during rapid proliferation and thereby predominantly activates the fatty acid synthase (FASN). Thus, FASN has become an attractive target of antineoplastic therapies. So far, most of the newly developed drugs inhibiting the lipid metabolism showed side toxicities or low solubility. Testing a novel promising epigallocatechin-3-gallate based compound, we found that it induced a metabolic switch from oxidative phosphorylation to glycolysis and ultimately induced glucose-dependent cell death in ovarian cancer cells. The cytotoxic effect of FASN inhibition was accompanied by a strong upregulation of HIF-1alpha and its downstream target REDD-1, a protein with a critical role in inhibiting mTOR during hypoxia. Intrigued by the fact that general hallmarks of cancer survival and aggressiveness like hypoxia and glycolysis were connected with cell death, we extended our study to better understand the metabolic mechanism leading to cell death. We present data on drastic metabolic alterations which included citrate, α-ketoglutarate and succinate and were induced by genetic or biochemical inhibition of FASN, revealing a novel powerful anticancer strategy. doi:10.1016/j.bbabio.2016.04.349