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One-carbon metabolism for cancer diagnostic and therapeutic approaches
Journal Pre-proof One-Carbon Metabolism for Cancer Diagnostic and Therapeutic Approaches Ayumu Asai, Masamitsu Konno, Jun Koseki, Masateru Taniguchi, Andrea Vecchione, Hideshi Ishii PII:
S0304-3835(19)30578-6
DOI:
https://doi.org/10.1016/j.canlet.2019.11.023
Reference:
CAN 114576
To appear in:
Cancer Letters
Received Date: 2 September 2019 Revised Date:
8 November 2019
Accepted Date: 18 November 2019
Please cite this article as: A. Asai, M. Konno, J. Koseki, M. Taniguchi, A. Vecchione, H. Ishii, OneCarbon Metabolism for Cancer Diagnostic and Therapeutic Approaches, Cancer Letters, https:// doi.org/10.1016/j.canlet.2019.11.023. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier B.V. All rights reserved.
One-Carbon Metabolism for Cancer Diagnostic and Therapeutic Approaches Ayumu Asai1,2,3, Masamitsu Konno2, Jun Koseki1, Masateru Taniguchi3, Andrea Vecchione4, Hideshi Ishii1
1
Department of Medical Data Science; Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan; 3 Artificial Intelligence Research Center, The Institute of Scientific and Industrial 2
Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka, 567-0047, Japan; 4 Department of Clinical and Molecular Medicine, University of Rome “Sapienza”, Santo Andrea Hospital, via di Grottarossa, Rome, 1035-00189, Italy.
Corresponding author: Hideshi Ishii, Department of Medical Data Science, Graduate School of medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel: +81-(0)6-6210-8406, 8406; Fax: +81-(0)6-6210-8407, 8407 E-mail: [email protected]
Keywords: Folate, Methionine, Methylation, DNA synthesis, Anticancer drugs
Highlights One-carbon metabolism has attracted particular attention in recent cancer research. Anticancer drugs targeting mitochondrial one-carbon metabolism have been developed. One-carbon metabolism is involved in the malignancy through methylation reactions on various substances. One-carbon metabolism is applicable to cancer diagnosis and cancer therapy.
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Abstract Altered metabolism is critical for the rapid and unregulated proliferation of cancer cells; hence the requirement for an abundant source of nucleotides. One characteristic of this metabolic reprogramming is in one-carbon (1C) metabolism, which is particularly noteworthy for its role in DNA synthesis. Various forms of methylation are also noteworthy as they relate to cancer cell survival and proliferation. In recent years, 1C metabolism has received substantial attention for its role in cancer malignancy via these functions. Therefore, therapeutic inhibitors targeting 1C metabolism have been utilized as anticancer drugs. This review outlines the importance of 1C metabolism and its clinical application in cancer. Understanding 1C metabolism could aid the development of novel cancer diagnostic and therapeutic methods.
Historical Research of One-Carbon Metabolism One-carbon (1C) metabolism is constructed by folate and methionine metabolism [1]. In 1922, methionine extraction from casein lead to the study of methionine metabolism; leading to the first observation of 1C metabolism [2, 3] (Fig. 1). In 1941, folic acid (as folate) was extracted from spinach [4]. In 1945 and 1957, dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS), respectively, were discovered as the main metabolic enzymes in folate metabolism [5, 6]. Since then, the relation between methionine metabolism and folate metabolism has been termed “one-carbon metabolism”. Cancer research into viable therapeutics took place in 1956 where it was revealed that folate and methionine cycles in contribution with 1C metabolism could be used in DNA synthesis [7]. Therefore, aminopterin [8], methotrexate [9, 10], and 5-fluorouracil [11] have been developed as anticancer drugs targeting 1C metabolism. As mentioned above, 1C metabolism was the most frequently studied mechanism for cancer cell proliferation in the 1940s and 1950s [12]. Furthermore, anticancer agents targeting 1C metabolism, such as gemcitabine and capecitabine, have been developed to inhibit DNA synthesis [13, 14]. The importance of 1C metabolism in tumor tissues has been examined since 2005, and it has been revealed to influence the overall prognosis in certain cancers [15-19]. Furthermore, S-adenosylmethionine (SAM) was identified in 1952 [20], and the relation of 1C metabolism to methylation of DNA, RNA, and histones was revealed by around 2
1970 [21-23]. Nonetheless, the importance of 1C metabolism in cancer cells remains unclear. Fortunately, since around 2010, it has been reported that methylation of DNA, RNA, and histones are involved in cancer malignancy [24-26]. Moreover, it has recently been reported that 1C metabolism (especially folate metabolism in mitochondria), is a critical mechanism involved in cancer cell survival and proliferation. For example, two notable enzymes, methylenetetrahydrofolate dehydrogenase (MTHFD2) and serine hydroxymethyltransferase (SHMT2) are markedly higher in cancer cell lines and in tumor tissues of cancer patients [27-30]. Given these results, anticancer drugs targeting MTHFD2 or SHMT2 are currently being investigated [31, 32]. Therefore, 1C metabolism has garnered much attention as a viable target for cancer therapy.
1C Metabolism as a Source for DNA Synthesis DNA consists of two strands with each strand being composed of nucleic acids bonded together by a phosphodiester backbone, where two strands are hydrogen bonded together to form a double helix. There are four nucleic acids within DNA: two pyrimidine bases and two purine bases. During 1C metabolism, pyrimidine bases and purine bases are biosynthesized by transferring a single carbon from serine [29,33]; hence, the importance of serine in nucleotide synthesis. Serine is synthesized from 3-phosphoglycerate (3-PG) during glycolysis and supplies folate metabolism [34] (Fig. 2A). One carbon derived from serine is transferred to tetrahydrofolate producing 5,10-methylenetetrahydrofolate (CH2-THF) (Fig. 2B), which is critical for pyrimidine synthesis [7]. Subsequently, CH2-THF is converted to 10-formyltetrahydrofolate (CHO-THF), which is critical for purine synthesis [7]. Thus, these metabolites are essential for pyrimidine and purine synthesis. Since such DNA synthesis is essential for cell survival, 1C metabolism has been a focus as a target for anticancer drugs and antibiotics. 1C metabolism is important for cells with a high proliferation rate (e.g. cancer cells and bacteria), due to the requirement of an abundance of DNA nucleotides. Therefore, 1C metabolism is a promising target for cell proliferation inhibition. 1C metabolism occurs within the cytoplasm, where pyrimidines and purines are synthesized, as well as in the mitochondria [29]. Thus, it is not surprising that targets of 1C metabolism inhibitors such as DHFR or TYMS are mostly found in 3
the cytoplasm (Fig. 3A, B). Anticancer drugs targeting mitochondrial 1C metabolism have not been clinically applied (Fig. 3B). Nonetheless, in recent years, mitochondrial folate metabolism has attracted the attention as a potential cancer therapeutic due to its observable increase in cancer cell lines and cancer patients [29, 30]. Additionally, it has been indicated that mitochondrial folate metabolism affects the prognosis of cancer patients more significantly than do targets of currently used anticancer drugs, such as DHFR or TYMS [17, 32]. Furthermore, it was indicated that depletion of serine or inhibition of specific mitochondrial folate metabolic enzymes reduced the level of purine nucleotides, consequently inhibiting proliferation [35-37]. Therefore, anticancer drugs targeting mitochondrial 1C metabolism are currently being investigated [31, 32]. In addition, 1C metabolism is involved in reduction-oxidation (redox) reactions by producing glutathione [1]. It was reported that SHMT2 in 1C metabolism was induced in hypoxia and supports tumor growth by mitochondrial redox reactions [38]. Many anticancer drugs targeting 1C metabolism have been applied for colorectal, lung, and breast cancers (Fig. 3B). These cancers are reported to be highly hypoxic [39]. Anticancer drugs targeting 1C metabolism may play a role in releasing the adaptation of tumor tissues to the hypoxic environment in addition to the suppression of DNA synthesis. Moreover, specific biomarkers have been discovered to play a role in predicting the chemosensitivity to anticancer drugs targeting 1C metabolism (Fig. 3C). This leads to be easy to use anticancer drugs targeting 1C metabolism. As above, 1C metabolism is predicted to gain further attention as a target of anticancer drugs in the future.
1C Metabolism Involved in Protein Synthesis Methionine, the first amino acid encoded within a polypeptide chain, generally plays a role in the pathway of 1C metabolism, by making methionine essential for protein synthesis [40]. Considering the importance of methionine as a start amino acid, we note that restriction of methionine inhibits protein synthesis, leading to a critical effect on cell growth, as reported in the study of breast cancer cells [41]. Eventually, methionine plays several roles during protein synthesis, such as ribosomal construction, histone methylation, and activation of some important pathways (e.g., mTOR signal pathway [42], P38 mitogen-activated protein MAP kinases [43] and oxidative stress-dependent pathways [44]). Among them, 4
mTOR signal is one of the most frequently reported signals related to protein synthesis. SAM, a product from methionine, activates the mTOR signal by binding to SAMTOR [42]. mTOR signal regulates various components involved in protein synthesis, including initiation and elongation factors, and the biogenesis of ribosomes themselves [45]. mTOR signal also activates de novo synthesis of serine, a carbon donor in 1C metabolism [46], whereas SAM is a source of polyamine synthesis [47]. Previous studies reported that polyamine is involved in translation of proteins with polyamine-responsive modulon [48], and that 5′-methylthioadenosine generated in polyamine synthesis process is recycled as methionine via salvage pathway [49]. Although many tumors lack methylthioadenosine phosphorylase and show insufficient flow in the salvage pathway [50], how C1 metabolism is controlled by methionine and serine remains to be understood fully. Methionine is an essential amino acid as nutrition, unlike serine and glycine as non-essential amino acids [51]. Essential amino acids including methionine can be synthesized in prokaryotes and protists [52]; biosynthesis of essential amino acids in prokaryotes and protists requires multi-step synthetic pathways rather than biosynthesis of non-essential amino acids [52]. Given that essential amino acids usually are contained in food, it is considered that eukaryotes including humans have lost the ability to synthesize essential amino acids during evolution [53], and that essential amino acids must be taken from foods for survive and growth in eukaryotes. Reportedly, the requirement of methionine in cysteine is 19 mg/kg body weight/day for adult [54]; food sources highly containing methionine are eggs, meat and fish [55]. However, the studies in mice, rats and Drosophila showed that restriction of methionine can increase lifespan and inhibit colon carcinogenesis and aging-related diseases [56-58]. Considering that excess methionine causes adverse events, the organisms may have adapted without synthesizing methionine as essential amino acids. In a healthy life, it is important that the 1C metabolism is controlled through an appropriate diet.
1C Metabolism Role in Various Methylation Reactions In general, cells are constructed based on DNA information [59]. DNA information is transcribed to mRNA, followed by translation to proteins. These processes determine a cell’s overall fate and function. In addition, transcription and 5
translation are regulated by modifications of DNA, RNA, proteins, and certain metabolites [60]. For example, methylation of DNA, RNA, and histones are reported to be important modifiers in biological process regulation [61]. Therefore, 1C metabolism, the source of methylation, plays an important role in determining the fate and function of a cell. The process of carbon transfer via 1C metabolism is as follows: CH2-THF is converted to 5-methyltetrahydrofolate (CH3-THF); then, the methyl unit is passed to homocysteine during methionine metabolism, producing methionine; and finally, the methionine is adenosylated to produce SAM, a universal methyl donor in methylation of DNA, RNA, and histones [62] (Fig. 4A). To date, DNA methylation is the most studied nucleic acid modification. DNA methylation mainly occurs at the 5’ carbon of the pyrimidine base, cytosine (5mC) in CpG islands [63, 64]. DNA methylation is catalyzed by DNA methyltransferases (DNMTs) such as DNMT1, DNMT3a, and DNMT3b [65]. Methylated CpG islands in the promoter region of a gene induces gene silencing and stabilizes the chromosomal structure [66, 67]. Therefore, DNA methylation is important for regulating gene expression as an epigenome. Recently, RNA methylation has been attracting attention, especially in cancer and stem cell research. RNA methylation mainly occurs at the N6 position of an adenine base (m6A) in near stop codons [68, 69]. RNA methylation is catalyzed by RNA methyltransferases such as METTL3, METTL14, and WTAP [70]. The function of m6A is dependent on the YTH-family, as readers of m6A. YTHDF1 and YTHDF3 recognize m6A near the stop codon, thereby initiating the translation of a recognized gene via eIF3 [71]. By contrast, YTHDF2 recognizes m6A and effects degradation of the target gene [69,72]. In addition, YTHDC1 recognizes m6A in CDS regions to initiate splicing via SRSF3 [73, 74]. RNA methylation is a multi-functional event and needs to be examined with respect to not only the methylation status but also the sites and the readers of methylation. Histone methylation has been studied frequently as one of protein modification, especially for its role in gene expression. Histone methylation mainly occurs at the 4th, 9th, 20th, 27th, 36th, and 79th positions, respectively, of lysine residues in H3 proteins (H3K4, H3K9, H3K20, H3K27, H3K36, and H3K79). Increased methylation of H3K9, H3K20, and H3K27 specifically represses transcription: on the contrary, increased methylation of H3K4, H3K36, H3K79 often activates transcription [75]. The methyl markings are diverse; for examples, mono-methylation is found in enhancer regions, whereas tri-methylation is 6
located in promoter regions of genes. Those are modulated by the protein complex, histone methyltransferases (HMTs), such as MLL2 and EZH2, which catalyze histone methylation. Therefore, it is important to investigate which regions of DNA are recognizable positions for histone methylation. Although SAM has a role in methylation, it is also involved in polyamine metabolism. For example, putrescine produces spermidine from SAM, and spermidine further produces spermine from SAM. These reactions are catalyzed by polyamine synthases (PASs) such as spermidine synthase and spermine synthase. It has been reported that polyamines play important roles in many cellular processes such as regulation of transcription and translation [76-79]. As mentioned above, these methylation reactions are important processes that affect a cell’s characterization and function, with 1C metabolism being one of the main determining factors.
Cancer Malignancy via Various Forms of Methylation Enhanced folate metabolism in cancer cells generates an abundance of methyl units and adenosine as materials for methionine metabolism, revealing that methionine metabolism is enhanced in cancer cells. Thus, methionine is highly consumed in cancer cells compared with normal cells, and some cancer cells cannot grow in the absence of methionine [80, 81]. Defects of methionine metabolism reduce intracellular SAM levels, affecting histone methylation dynamics [82-84]. Therefore, methionine metabolism may not only be important for histone methylation, but also epi-genome and epi-transcriptome. Suggesting that cancer cells may significantly change the epi-genome and epi-transcriptome profiles by boosting methylation reactions via increased activity of 1C metabolism. Hypermethylation in DNA has been reported in various tumor cells such as breast, colon, and cervical cancer cells [85]. Hyper-methylation of promoters in tumor-suppressor genes induce the reduction of their gene expression. It is worth mentioning that DNA methylation has been found to be correlated with oncogene or tumor suppressor gene expression [24, 85]. Such a correlation has been integrated into clinical practice, as seen in several clinical kits in production for detecting DNA methylation in cancer patients (Fig. 4B). In addition, it has been reported that hypermethylation of DNA is related to chemoresistance [86]. Thus,
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DNA methylation is important not only for its molecular biological roles, but also as a clinical biomarker. N⁶-Methyl adenosine (m6A) in RNA exerts multiple functions in cancer initiation and progression. In human acute myeloid leukemia (AML), METTL3 activity increases and augments MYC, BCL2, and PTEN by promoting the translation of these mRNAs [25]. Similarly, it has been reported that RNA methylation promotes tumor growth in breast cancer, hepatocellular carcinoma, colorectal cancer, and pancreatic cancer [87-90]. Additionally, RNA methylation has been reported as an effective diagnostic factor for gastrointestinal cancers [91]. However, RNA methylation has been shown to function as a tumor suppressor (as seen in glioblastoma) [92]; but evidence has also shown that RNA methylation is involved in tumor immunity. For example, RNA methylation controls T-cell homeostasis by regulating the IL-7/STAT5/SOCS pathway, suggesting their involvement in tumor immune system communication and importance in tumor growth [93]. The function of RNA methylation in cancer needs to be further investigated for each cancer type and environment. In cancer cells, depletion of SAM affects histone methylation dynamics and growth [80-84]. It has been reported that methylation of H3K4 affects cell fate genes and cancer-associated genes, including AKT1, MYC, and MAPK [81]. In addition, mutations of histone methyltransferases MLL2, EZH2, and histone demethylase UTX can result in abnormal histone methylation and altered gene expression [94, 95]. Moreover, histone demethylation via LSD1 or Jumonji C domain families are important for cancer stem cells (CSCs) in various cancer types [96-98]. As described above, both histone methylation and demethylation play important roles in cancer cells. Methylation derived from SAM is involved in polyamine metabolism [1], where polyamine regulates cell proliferation and cancer progression [99]. In CSCs, especially, it has been reported that polyamine is accumulated by increased ornithine decarboxylase activity and drives epigenetic control for cancer stemness [100-103]. In addition, it was also reported that CSCs can survive against certain anticancer drugs by adjusting the amount of polyamine present [104]. As described above, various forms of methylation via enhanced 1C metabolism regulate malignancy in cancer cells.
Supplementation of Folate for Cancer Therapy 8
In general, folate deficiency is known to induce neural tube defects [105]. For cancer cells, there is evidence suggesting folate plays a dual role in both prevention of carcinogenesis and development of preneoplastic lesions. For example, in two colorectal cancer mouse models, supplementation of folate in mice without preneoplastic lesions suppressed the development and progression of colorectal cancer [106, 107]. However, for the mice with preneoplastic lesions, supplementation of folate increased the development and progression of colorectal cancer [106, 107]. Yet, such time-dependent functions of folate remain unclear. Folate deficiency may result from the reduced production of thymidine as well as the misincorporation of uracil into DNA [108, 109]. Before carcinogenesis, supplementation of folate may prevent the misincorporation of uracil into DNA by folate deficiency. Notwithstanding, folate supplementation in folate-deficient cells has shown tumorigenesis and aggressive growth of cancer cells [110]. Therefore, for the prevention and therapy of cancer, the relationship between folate and cancer needs to be further studied.
In conclusion, although 1C metabolism is well-documented and has been used clinically for quite some time, it has recently gained considerable attention because of its impact on various biological processes and importance in cancer. 1C metabolism has already contributed significantly to cancer diagnosis and therapy (Fig. 5). Although therapeutic approaches against DNA synthesis and diagnostic tool for DNA methylation have been developed, they remain to be investigated further for efficient cancer medicine [111, 112]. Also, recent studies of epigenetic drugs opened an avenue to therapeutic targets of histone methylation, such as KDM1/Ezh2 [113] and KDM5B/Jarid1B [96]. Furthermore, the recent progress of sequencing technology allowed the identification of significant fingerprints of RNA methylation in tumors [91, 114]. Moreover, the studies of polyamine flux may give specific targets against cancer stem cells, for examples, via controlling of H3 histone modifications and gene expression [96, 103]. In order to discover promising targets as a source of methyl unit, the mechanism studies of their upstream will be necessary. Finally, given that cancer is a genetic disease with numerous DNA mutations accumulated in each cancer cell, genome-wide comprehensive studies for genotype and phenotype correlations will be indispensable for the full understanding cancer. Therefore, it is undoubtedly true that further studies are needed to gain further understanding 9
of 1C metabolism, considering that this metabolic pathway has great implications on the understanding of cancer diagnosis and therapy.
Conflicts of interest Institutional endowments were received partially from Taiho Pharmaceutical Co., Ltd.; Unitech Co., Ltd. (Chiba, Japan); IDEA Consultants, Inc. (Tokyo, Japan); and Kinshu-kai Medical Corporation (Osaka, Japan) [HI]; Chugai Co., Ltd.; Yakult Honsha Co., Ltd.; and Ono Pharmaceutical Co., Ltd [MK].
Acknowledgement This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (15H05791; 17H04282; 17K19698; 18K16356; 18K16355; 18KK0251; 19K22658; 19K09172; 19K07688); AMED, Japan (16cm0106414h0001; 17cm0106414h0002). Partial support was received from Takeda Science Foundation, Senri Life Science Foundation, Osaka Cancer Society, Princess Takamatsu Cancer Research Fund, Yasuda Medical, Pancreas Research Foundation, and Nakatomi Foundation of Japan, Suzuken Memorial Foundation.
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Figure caption Figure 1 Historical View of Research on 1C Metabolism. The first reports on 1C metabolism are described along with the year of publication. Vertical axis, concept; Horizontal axis, time; Red circle, 1C metabolism; Green circle, folate metabolism; Blue circle, methionine metabolism; 1C, one carbon; DHFR, dihydrofolate reductase; 5-FU, 5-fluorouracil; MTHFD, methylenetetrahydrofolate dehydrogenase; SHMT, serine hydroxymethyltransferse; TYMS, thymidylate synthetase.
Figure 2 1C Metabolism in DNA Synthesis. (A) Positioning of 1C metabolism in cell metabolism. 1C metabolism is a metabolic pathway linked to glycolysis through the synthesis of serine from 3-phosphoglyceric acid (3-PG). 1C metabolism is coupled with folate metabolism and methionine metabolism and occurs in the cytoplasm and mitochondria. (B) 1C metabolism is involved in DNA synthesis. 21
Folate metabolism, a type of 1C metabolism, results in the synthesis of pyrimidine nucleotides and purine nucleotides. 3-PG, 3-phosphoglycerate; ETC, electron transport chain; THF, tetrahydrofolate; MET, methionine; SAM, S-adenosyl methionine; SAH, S-adenosyl-L-homocysteine; hCYS, homocysteine.
Figure 3 Inhibitors Targeting 1C Metabolism. (A) The targets of 1C metabolism inhibitors. Most inhibitors target cytoplasmic 1C metabolism. Red frame, targets for approved drugs; Blue frame, targets of drugs under development; Thick arrows, pathways that are promoted in cancer. (B) List of the inhibitors targeting 1C metabolism. Most inhibitors target TYMS or DHFR as anticancer drugs and antibiotics. (C) Biomarkers indicating 1C metabolism inhibition by the targeted inhibitors. Biomarkers for 1C metabolism inhibition by targeting nucleic acid synthesis. OPRT, orotate phosphoribosyltransferase; DPD, dihydropyrimidine dehydrogenase.
Figure 4 Methylations via 1C Metabolism in Cancer. (A) Various methylation pathways in cancer regulated by SAM, which is derived from 1C metabolism. SAM is a cosubstrate for methylation of DNA, RNA, and histones. Cancer promotes malignancy via these forms of methylation. (B) Cancer diagnosis by detection of DNA methylation. Commercial kits for detecting DNA methylation are listed. SAM, S-adenosyl methionine; DNMTs, DNA methyltransferases; METTLs, methyltransferase-like family; HMTs, histone methyltransferases.
Figure 5 1C Metabolism for Cancer Diagnosis and Therapy. For diagnosis of carcinogenesis and predicting sensitivity to anticancer drugs, enhancement of DNA synthesis and methylation by 1C metabolism can be used as a biomarker. For cancer therapy, 1C metabolism can be used to target both the high DNA synthesis and the epigenome involved in cancer malignancy. 1C metabolism is expected to have significant applications in both cancer diagnosis and therapy. 22
Highlights One-carbon metabolism has attracted particular attention in recent cancer research. Anticancer drugs targeting mitochondrial one-carbon metabolism have been developed. One-carbon metabolism is involved in the malignancy through methylation reactions on various substances. One-carbon metabolism is applicable to cancer diagnosis and cancer therapy.
Conflicts of interest Institutional endowments were received partially from Taiho Pharmaceutical Co., Ltd.; Unitech Co., Ltd. (Chiba, Japan); IDEA Consultants, Inc. (Tokyo, Japan); and Kinshu-kai Medical Corporation (Osaka, Japan) [HI]; Chugai Co., Ltd.; Yakult Honsha Co., Ltd.; and Ono Pharmaceutical Co., Ltd [MK].
S0304-3835(19)30578-6
DOI:
https://doi.org/10.1016/j.canlet.2019.11.023
Reference:
CAN 114576
To appear in:
Cancer Letters
Received Date: 2 September 2019 Revised Date:
8 November 2019
Accepted Date: 18 November 2019
Please cite this article as: A. Asai, M. Konno, J. Koseki, M. Taniguchi, A. Vecchione, H. Ishii, OneCarbon Metabolism for Cancer Diagnostic and Therapeutic Approaches, Cancer Letters, https:// doi.org/10.1016/j.canlet.2019.11.023. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier B.V. All rights reserved.
One-Carbon Metabolism for Cancer Diagnostic and Therapeutic Approaches Ayumu Asai1,2,3, Masamitsu Konno2, Jun Koseki1, Masateru Taniguchi3, Andrea Vecchione4, Hideshi Ishii1
1
Department of Medical Data Science; Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Japan; 3 Artificial Intelligence Research Center, The Institute of Scientific and Industrial 2
Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka, 567-0047, Japan; 4 Department of Clinical and Molecular Medicine, University of Rome “Sapienza”, Santo Andrea Hospital, via di Grottarossa, Rome, 1035-00189, Italy.
Corresponding author: Hideshi Ishii, Department of Medical Data Science, Graduate School of medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel: +81-(0)6-6210-8406, 8406; Fax: +81-(0)6-6210-8407, 8407 E-mail: [email protected]
Keywords: Folate, Methionine, Methylation, DNA synthesis, Anticancer drugs
Highlights One-carbon metabolism has attracted particular attention in recent cancer research. Anticancer drugs targeting mitochondrial one-carbon metabolism have been developed. One-carbon metabolism is involved in the malignancy through methylation reactions on various substances. One-carbon metabolism is applicable to cancer diagnosis and cancer therapy.
1
Abstract Altered metabolism is critical for the rapid and unregulated proliferation of cancer cells; hence the requirement for an abundant source of nucleotides. One characteristic of this metabolic reprogramming is in one-carbon (1C) metabolism, which is particularly noteworthy for its role in DNA synthesis. Various forms of methylation are also noteworthy as they relate to cancer cell survival and proliferation. In recent years, 1C metabolism has received substantial attention for its role in cancer malignancy via these functions. Therefore, therapeutic inhibitors targeting 1C metabolism have been utilized as anticancer drugs. This review outlines the importance of 1C metabolism and its clinical application in cancer. Understanding 1C metabolism could aid the development of novel cancer diagnostic and therapeutic methods.
Historical Research of One-Carbon Metabolism One-carbon (1C) metabolism is constructed by folate and methionine metabolism [1]. In 1922, methionine extraction from casein lead to the study of methionine metabolism; leading to the first observation of 1C metabolism [2, 3] (Fig. 1). In 1941, folic acid (as folate) was extracted from spinach [4]. In 1945 and 1957, dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS), respectively, were discovered as the main metabolic enzymes in folate metabolism [5, 6]. Since then, the relation between methionine metabolism and folate metabolism has been termed “one-carbon metabolism”. Cancer research into viable therapeutics took place in 1956 where it was revealed that folate and methionine cycles in contribution with 1C metabolism could be used in DNA synthesis [7]. Therefore, aminopterin [8], methotrexate [9, 10], and 5-fluorouracil [11] have been developed as anticancer drugs targeting 1C metabolism. As mentioned above, 1C metabolism was the most frequently studied mechanism for cancer cell proliferation in the 1940s and 1950s [12]. Furthermore, anticancer agents targeting 1C metabolism, such as gemcitabine and capecitabine, have been developed to inhibit DNA synthesis [13, 14]. The importance of 1C metabolism in tumor tissues has been examined since 2005, and it has been revealed to influence the overall prognosis in certain cancers [15-19]. Furthermore, S-adenosylmethionine (SAM) was identified in 1952 [20], and the relation of 1C metabolism to methylation of DNA, RNA, and histones was revealed by around 2
1970 [21-23]. Nonetheless, the importance of 1C metabolism in cancer cells remains unclear. Fortunately, since around 2010, it has been reported that methylation of DNA, RNA, and histones are involved in cancer malignancy [24-26]. Moreover, it has recently been reported that 1C metabolism (especially folate metabolism in mitochondria), is a critical mechanism involved in cancer cell survival and proliferation. For example, two notable enzymes, methylenetetrahydrofolate dehydrogenase (MTHFD2) and serine hydroxymethyltransferase (SHMT2) are markedly higher in cancer cell lines and in tumor tissues of cancer patients [27-30]. Given these results, anticancer drugs targeting MTHFD2 or SHMT2 are currently being investigated [31, 32]. Therefore, 1C metabolism has garnered much attention as a viable target for cancer therapy.
1C Metabolism as a Source for DNA Synthesis DNA consists of two strands with each strand being composed of nucleic acids bonded together by a phosphodiester backbone, where two strands are hydrogen bonded together to form a double helix. There are four nucleic acids within DNA: two pyrimidine bases and two purine bases. During 1C metabolism, pyrimidine bases and purine bases are biosynthesized by transferring a single carbon from serine [29,33]; hence, the importance of serine in nucleotide synthesis. Serine is synthesized from 3-phosphoglycerate (3-PG) during glycolysis and supplies folate metabolism [34] (Fig. 2A). One carbon derived from serine is transferred to tetrahydrofolate producing 5,10-methylenetetrahydrofolate (CH2-THF) (Fig. 2B), which is critical for pyrimidine synthesis [7]. Subsequently, CH2-THF is converted to 10-formyltetrahydrofolate (CHO-THF), which is critical for purine synthesis [7]. Thus, these metabolites are essential for pyrimidine and purine synthesis. Since such DNA synthesis is essential for cell survival, 1C metabolism has been a focus as a target for anticancer drugs and antibiotics. 1C metabolism is important for cells with a high proliferation rate (e.g. cancer cells and bacteria), due to the requirement of an abundance of DNA nucleotides. Therefore, 1C metabolism is a promising target for cell proliferation inhibition. 1C metabolism occurs within the cytoplasm, where pyrimidines and purines are synthesized, as well as in the mitochondria [29]. Thus, it is not surprising that targets of 1C metabolism inhibitors such as DHFR or TYMS are mostly found in 3
the cytoplasm (Fig. 3A, B). Anticancer drugs targeting mitochondrial 1C metabolism have not been clinically applied (Fig. 3B). Nonetheless, in recent years, mitochondrial folate metabolism has attracted the attention as a potential cancer therapeutic due to its observable increase in cancer cell lines and cancer patients [29, 30]. Additionally, it has been indicated that mitochondrial folate metabolism affects the prognosis of cancer patients more significantly than do targets of currently used anticancer drugs, such as DHFR or TYMS [17, 32]. Furthermore, it was indicated that depletion of serine or inhibition of specific mitochondrial folate metabolic enzymes reduced the level of purine nucleotides, consequently inhibiting proliferation [35-37]. Therefore, anticancer drugs targeting mitochondrial 1C metabolism are currently being investigated [31, 32]. In addition, 1C metabolism is involved in reduction-oxidation (redox) reactions by producing glutathione [1]. It was reported that SHMT2 in 1C metabolism was induced in hypoxia and supports tumor growth by mitochondrial redox reactions [38]. Many anticancer drugs targeting 1C metabolism have been applied for colorectal, lung, and breast cancers (Fig. 3B). These cancers are reported to be highly hypoxic [39]. Anticancer drugs targeting 1C metabolism may play a role in releasing the adaptation of tumor tissues to the hypoxic environment in addition to the suppression of DNA synthesis. Moreover, specific biomarkers have been discovered to play a role in predicting the chemosensitivity to anticancer drugs targeting 1C metabolism (Fig. 3C). This leads to be easy to use anticancer drugs targeting 1C metabolism. As above, 1C metabolism is predicted to gain further attention as a target of anticancer drugs in the future.
1C Metabolism Involved in Protein Synthesis Methionine, the first amino acid encoded within a polypeptide chain, generally plays a role in the pathway of 1C metabolism, by making methionine essential for protein synthesis [40]. Considering the importance of methionine as a start amino acid, we note that restriction of methionine inhibits protein synthesis, leading to a critical effect on cell growth, as reported in the study of breast cancer cells [41]. Eventually, methionine plays several roles during protein synthesis, such as ribosomal construction, histone methylation, and activation of some important pathways (e.g., mTOR signal pathway [42], P38 mitogen-activated protein MAP kinases [43] and oxidative stress-dependent pathways [44]). Among them, 4
mTOR signal is one of the most frequently reported signals related to protein synthesis. SAM, a product from methionine, activates the mTOR signal by binding to SAMTOR [42]. mTOR signal regulates various components involved in protein synthesis, including initiation and elongation factors, and the biogenesis of ribosomes themselves [45]. mTOR signal also activates de novo synthesis of serine, a carbon donor in 1C metabolism [46], whereas SAM is a source of polyamine synthesis [47]. Previous studies reported that polyamine is involved in translation of proteins with polyamine-responsive modulon [48], and that 5′-methylthioadenosine generated in polyamine synthesis process is recycled as methionine via salvage pathway [49]. Although many tumors lack methylthioadenosine phosphorylase and show insufficient flow in the salvage pathway [50], how C1 metabolism is controlled by methionine and serine remains to be understood fully. Methionine is an essential amino acid as nutrition, unlike serine and glycine as non-essential amino acids [51]. Essential amino acids including methionine can be synthesized in prokaryotes and protists [52]; biosynthesis of essential amino acids in prokaryotes and protists requires multi-step synthetic pathways rather than biosynthesis of non-essential amino acids [52]. Given that essential amino acids usually are contained in food, it is considered that eukaryotes including humans have lost the ability to synthesize essential amino acids during evolution [53], and that essential amino acids must be taken from foods for survive and growth in eukaryotes. Reportedly, the requirement of methionine in cysteine is 19 mg/kg body weight/day for adult [54]; food sources highly containing methionine are eggs, meat and fish [55]. However, the studies in mice, rats and Drosophila showed that restriction of methionine can increase lifespan and inhibit colon carcinogenesis and aging-related diseases [56-58]. Considering that excess methionine causes adverse events, the organisms may have adapted without synthesizing methionine as essential amino acids. In a healthy life, it is important that the 1C metabolism is controlled through an appropriate diet.
1C Metabolism Role in Various Methylation Reactions In general, cells are constructed based on DNA information [59]. DNA information is transcribed to mRNA, followed by translation to proteins. These processes determine a cell’s overall fate and function. In addition, transcription and 5
translation are regulated by modifications of DNA, RNA, proteins, and certain metabolites [60]. For example, methylation of DNA, RNA, and histones are reported to be important modifiers in biological process regulation [61]. Therefore, 1C metabolism, the source of methylation, plays an important role in determining the fate and function of a cell. The process of carbon transfer via 1C metabolism is as follows: CH2-THF is converted to 5-methyltetrahydrofolate (CH3-THF); then, the methyl unit is passed to homocysteine during methionine metabolism, producing methionine; and finally, the methionine is adenosylated to produce SAM, a universal methyl donor in methylation of DNA, RNA, and histones [62] (Fig. 4A). To date, DNA methylation is the most studied nucleic acid modification. DNA methylation mainly occurs at the 5’ carbon of the pyrimidine base, cytosine (5mC) in CpG islands [63, 64]. DNA methylation is catalyzed by DNA methyltransferases (DNMTs) such as DNMT1, DNMT3a, and DNMT3b [65]. Methylated CpG islands in the promoter region of a gene induces gene silencing and stabilizes the chromosomal structure [66, 67]. Therefore, DNA methylation is important for regulating gene expression as an epigenome. Recently, RNA methylation has been attracting attention, especially in cancer and stem cell research. RNA methylation mainly occurs at the N6 position of an adenine base (m6A) in near stop codons [68, 69]. RNA methylation is catalyzed by RNA methyltransferases such as METTL3, METTL14, and WTAP [70]. The function of m6A is dependent on the YTH-family, as readers of m6A. YTHDF1 and YTHDF3 recognize m6A near the stop codon, thereby initiating the translation of a recognized gene via eIF3 [71]. By contrast, YTHDF2 recognizes m6A and effects degradation of the target gene [69,72]. In addition, YTHDC1 recognizes m6A in CDS regions to initiate splicing via SRSF3 [73, 74]. RNA methylation is a multi-functional event and needs to be examined with respect to not only the methylation status but also the sites and the readers of methylation. Histone methylation has been studied frequently as one of protein modification, especially for its role in gene expression. Histone methylation mainly occurs at the 4th, 9th, 20th, 27th, 36th, and 79th positions, respectively, of lysine residues in H3 proteins (H3K4, H3K9, H3K20, H3K27, H3K36, and H3K79). Increased methylation of H3K9, H3K20, and H3K27 specifically represses transcription: on the contrary, increased methylation of H3K4, H3K36, H3K79 often activates transcription [75]. The methyl markings are diverse; for examples, mono-methylation is found in enhancer regions, whereas tri-methylation is 6
located in promoter regions of genes. Those are modulated by the protein complex, histone methyltransferases (HMTs), such as MLL2 and EZH2, which catalyze histone methylation. Therefore, it is important to investigate which regions of DNA are recognizable positions for histone methylation. Although SAM has a role in methylation, it is also involved in polyamine metabolism. For example, putrescine produces spermidine from SAM, and spermidine further produces spermine from SAM. These reactions are catalyzed by polyamine synthases (PASs) such as spermidine synthase and spermine synthase. It has been reported that polyamines play important roles in many cellular processes such as regulation of transcription and translation [76-79]. As mentioned above, these methylation reactions are important processes that affect a cell’s characterization and function, with 1C metabolism being one of the main determining factors.
Cancer Malignancy via Various Forms of Methylation Enhanced folate metabolism in cancer cells generates an abundance of methyl units and adenosine as materials for methionine metabolism, revealing that methionine metabolism is enhanced in cancer cells. Thus, methionine is highly consumed in cancer cells compared with normal cells, and some cancer cells cannot grow in the absence of methionine [80, 81]. Defects of methionine metabolism reduce intracellular SAM levels, affecting histone methylation dynamics [82-84]. Therefore, methionine metabolism may not only be important for histone methylation, but also epi-genome and epi-transcriptome. Suggesting that cancer cells may significantly change the epi-genome and epi-transcriptome profiles by boosting methylation reactions via increased activity of 1C metabolism. Hypermethylation in DNA has been reported in various tumor cells such as breast, colon, and cervical cancer cells [85]. Hyper-methylation of promoters in tumor-suppressor genes induce the reduction of their gene expression. It is worth mentioning that DNA methylation has been found to be correlated with oncogene or tumor suppressor gene expression [24, 85]. Such a correlation has been integrated into clinical practice, as seen in several clinical kits in production for detecting DNA methylation in cancer patients (Fig. 4B). In addition, it has been reported that hypermethylation of DNA is related to chemoresistance [86]. Thus,
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DNA methylation is important not only for its molecular biological roles, but also as a clinical biomarker. N⁶-Methyl adenosine (m6A) in RNA exerts multiple functions in cancer initiation and progression. In human acute myeloid leukemia (AML), METTL3 activity increases and augments MYC, BCL2, and PTEN by promoting the translation of these mRNAs [25]. Similarly, it has been reported that RNA methylation promotes tumor growth in breast cancer, hepatocellular carcinoma, colorectal cancer, and pancreatic cancer [87-90]. Additionally, RNA methylation has been reported as an effective diagnostic factor for gastrointestinal cancers [91]. However, RNA methylation has been shown to function as a tumor suppressor (as seen in glioblastoma) [92]; but evidence has also shown that RNA methylation is involved in tumor immunity. For example, RNA methylation controls T-cell homeostasis by regulating the IL-7/STAT5/SOCS pathway, suggesting their involvement in tumor immune system communication and importance in tumor growth [93]. The function of RNA methylation in cancer needs to be further investigated for each cancer type and environment. In cancer cells, depletion of SAM affects histone methylation dynamics and growth [80-84]. It has been reported that methylation of H3K4 affects cell fate genes and cancer-associated genes, including AKT1, MYC, and MAPK [81]. In addition, mutations of histone methyltransferases MLL2, EZH2, and histone demethylase UTX can result in abnormal histone methylation and altered gene expression [94, 95]. Moreover, histone demethylation via LSD1 or Jumonji C domain families are important for cancer stem cells (CSCs) in various cancer types [96-98]. As described above, both histone methylation and demethylation play important roles in cancer cells. Methylation derived from SAM is involved in polyamine metabolism [1], where polyamine regulates cell proliferation and cancer progression [99]. In CSCs, especially, it has been reported that polyamine is accumulated by increased ornithine decarboxylase activity and drives epigenetic control for cancer stemness [100-103]. In addition, it was also reported that CSCs can survive against certain anticancer drugs by adjusting the amount of polyamine present [104]. As described above, various forms of methylation via enhanced 1C metabolism regulate malignancy in cancer cells.
Supplementation of Folate for Cancer Therapy 8
In general, folate deficiency is known to induce neural tube defects [105]. For cancer cells, there is evidence suggesting folate plays a dual role in both prevention of carcinogenesis and development of preneoplastic lesions. For example, in two colorectal cancer mouse models, supplementation of folate in mice without preneoplastic lesions suppressed the development and progression of colorectal cancer [106, 107]. However, for the mice with preneoplastic lesions, supplementation of folate increased the development and progression of colorectal cancer [106, 107]. Yet, such time-dependent functions of folate remain unclear. Folate deficiency may result from the reduced production of thymidine as well as the misincorporation of uracil into DNA [108, 109]. Before carcinogenesis, supplementation of folate may prevent the misincorporation of uracil into DNA by folate deficiency. Notwithstanding, folate supplementation in folate-deficient cells has shown tumorigenesis and aggressive growth of cancer cells [110]. Therefore, for the prevention and therapy of cancer, the relationship between folate and cancer needs to be further studied.
In conclusion, although 1C metabolism is well-documented and has been used clinically for quite some time, it has recently gained considerable attention because of its impact on various biological processes and importance in cancer. 1C metabolism has already contributed significantly to cancer diagnosis and therapy (Fig. 5). Although therapeutic approaches against DNA synthesis and diagnostic tool for DNA methylation have been developed, they remain to be investigated further for efficient cancer medicine [111, 112]. Also, recent studies of epigenetic drugs opened an avenue to therapeutic targets of histone methylation, such as KDM1/Ezh2 [113] and KDM5B/Jarid1B [96]. Furthermore, the recent progress of sequencing technology allowed the identification of significant fingerprints of RNA methylation in tumors [91, 114]. Moreover, the studies of polyamine flux may give specific targets against cancer stem cells, for examples, via controlling of H3 histone modifications and gene expression [96, 103]. In order to discover promising targets as a source of methyl unit, the mechanism studies of their upstream will be necessary. Finally, given that cancer is a genetic disease with numerous DNA mutations accumulated in each cancer cell, genome-wide comprehensive studies for genotype and phenotype correlations will be indispensable for the full understanding cancer. Therefore, it is undoubtedly true that further studies are needed to gain further understanding 9
of 1C metabolism, considering that this metabolic pathway has great implications on the understanding of cancer diagnosis and therapy.
Conflicts of interest Institutional endowments were received partially from Taiho Pharmaceutical Co., Ltd.; Unitech Co., Ltd. (Chiba, Japan); IDEA Consultants, Inc. (Tokyo, Japan); and Kinshu-kai Medical Corporation (Osaka, Japan) [HI]; Chugai Co., Ltd.; Yakult Honsha Co., Ltd.; and Ono Pharmaceutical Co., Ltd [MK].
Acknowledgement This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (15H05791; 17H04282; 17K19698; 18K16356; 18K16355; 18KK0251; 19K22658; 19K09172; 19K07688); AMED, Japan (16cm0106414h0001; 17cm0106414h0002). Partial support was received from Takeda Science Foundation, Senri Life Science Foundation, Osaka Cancer Society, Princess Takamatsu Cancer Research Fund, Yasuda Medical, Pancreas Research Foundation, and Nakatomi Foundation of Japan, Suzuken Memorial Foundation.
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Figure caption Figure 1 Historical View of Research on 1C Metabolism. The first reports on 1C metabolism are described along with the year of publication. Vertical axis, concept; Horizontal axis, time; Red circle, 1C metabolism; Green circle, folate metabolism; Blue circle, methionine metabolism; 1C, one carbon; DHFR, dihydrofolate reductase; 5-FU, 5-fluorouracil; MTHFD, methylenetetrahydrofolate dehydrogenase; SHMT, serine hydroxymethyltransferse; TYMS, thymidylate synthetase.
Figure 2 1C Metabolism in DNA Synthesis. (A) Positioning of 1C metabolism in cell metabolism. 1C metabolism is a metabolic pathway linked to glycolysis through the synthesis of serine from 3-phosphoglyceric acid (3-PG). 1C metabolism is coupled with folate metabolism and methionine metabolism and occurs in the cytoplasm and mitochondria. (B) 1C metabolism is involved in DNA synthesis. 21
Folate metabolism, a type of 1C metabolism, results in the synthesis of pyrimidine nucleotides and purine nucleotides. 3-PG, 3-phosphoglycerate; ETC, electron transport chain; THF, tetrahydrofolate; MET, methionine; SAM, S-adenosyl methionine; SAH, S-adenosyl-L-homocysteine; hCYS, homocysteine.
Figure 3 Inhibitors Targeting 1C Metabolism. (A) The targets of 1C metabolism inhibitors. Most inhibitors target cytoplasmic 1C metabolism. Red frame, targets for approved drugs; Blue frame, targets of drugs under development; Thick arrows, pathways that are promoted in cancer. (B) List of the inhibitors targeting 1C metabolism. Most inhibitors target TYMS or DHFR as anticancer drugs and antibiotics. (C) Biomarkers indicating 1C metabolism inhibition by the targeted inhibitors. Biomarkers for 1C metabolism inhibition by targeting nucleic acid synthesis. OPRT, orotate phosphoribosyltransferase; DPD, dihydropyrimidine dehydrogenase.
Figure 4 Methylations via 1C Metabolism in Cancer. (A) Various methylation pathways in cancer regulated by SAM, which is derived from 1C metabolism. SAM is a cosubstrate for methylation of DNA, RNA, and histones. Cancer promotes malignancy via these forms of methylation. (B) Cancer diagnosis by detection of DNA methylation. Commercial kits for detecting DNA methylation are listed. SAM, S-adenosyl methionine; DNMTs, DNA methyltransferases; METTLs, methyltransferase-like family; HMTs, histone methyltransferases.
Figure 5 1C Metabolism for Cancer Diagnosis and Therapy. For diagnosis of carcinogenesis and predicting sensitivity to anticancer drugs, enhancement of DNA synthesis and methylation by 1C metabolism can be used as a biomarker. For cancer therapy, 1C metabolism can be used to target both the high DNA synthesis and the epigenome involved in cancer malignancy. 1C metabolism is expected to have significant applications in both cancer diagnosis and therapy. 22
Highlights One-carbon metabolism has attracted particular attention in recent cancer research. Anticancer drugs targeting mitochondrial one-carbon metabolism have been developed. One-carbon metabolism is involved in the malignancy through methylation reactions on various substances. One-carbon metabolism is applicable to cancer diagnosis and cancer therapy.
Conflicts of interest Institutional endowments were received partially from Taiho Pharmaceutical Co., Ltd.; Unitech Co., Ltd. (Chiba, Japan); IDEA Consultants, Inc. (Tokyo, Japan); and Kinshu-kai Medical Corporation (Osaka, Japan) [HI]; Chugai Co., Ltd.; Yakult Honsha Co., Ltd.; and Ono Pharmaceutical Co., Ltd [MK].