Methionine uptake and metabolism is involved in a host of cellular functions including methylation reactions, redox maintenance, polyamine synthesis and coupling to folate metabolism, thus coordinating nucleotide and redox status. Each of these functions has been shown in many contexts to be relevant for cancer pathogenesis. Intriguingly, the levels of methionine obtained from the diet can have a large effect on cellular methionine metabolism. This establishes a link between nutrition and tumour cell metabolism that may allow for tumour-specific metabolic vulnerabilities that can be influenced by diet. Recently, a number of studies have begun to investigate the molecular and cellular mechanisms that underlie the interaction between nutrition, methionine metabolism and effects on health and cancer.
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DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).
Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).
Ducker, G. S. & Rabinowitz, J. D. One-carbon metabolism in health and disease. Cell Metab. 25, 27–42 (2017).
Kanarek, N. et al. Histidine catabolism is a major determinant of methotrexate sensitivity. Nature 559, 632–636 (2018).
Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018).
Knott, S. R. V. et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554, 378–381 (2018).
Xia, S. et al. Prevention of dietary-fat-fueled ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 25, 358–373 (2017).
Chan, W. K. et al. Glutaminase activity of L-asparaginase contributes to durable preclinical activity against acute lymphoblastic leukemia. Mol. Cancer Ther. 18, 1587–1592 (2019).
Nencioni, A., Caffa, I., Cortellino, S. & Longo, V. D. Fasting and cancer: molecular mechanisms and clinical application. Nat. Rev. Cancer 18, 707–719 (2018).
Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428–438 e425 (2018).
Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012).
Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 749 (2016).
Gwinn, D. M. et al. Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell 33, 91–107 e106 (2018).
Ruckenstuhl, C. et al. Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification. PLOS Genet. 10, e1004347 (2014).
Lee, B. C. et al. Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino-acid status. Nat. Commun. 5, 3592 (2014). This study and related work demonstrate the role of dietary methionine in determining lifespan.
Cabreiro, F. et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228–239 (2013).
Sun, L., Sadighi Akha, A. A., Miller, R. A. & Harper, J. M. Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age. J. Gerontol. A Biol. Sci. Med. Sci. 64, 711–722 (2009).
Miller, R. A. et al. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4, 119–125 (2005).
Orentreich, N., Matias, J. R., DeFelice, A. & Zimmerman, J. A. Low methionine ingestion by rats extends life span. J. Nutr. 123, 269–274 (1993).
Zimmerman, J. A., Malloy, V., Krajcik, R. & Orentreich, N. Nutritional control of aging. Exp. Gerontol. 38, 47–52 (2003).
Barcena, C. et al. Methionine restriction extends lifespan in progeroid mice and alters lipid and bile acid metabolism. Cell Rep. 24, 2392–2403 (2018).
Malloy, V. L. et al. Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice. Metabolism 62, 1651–1661 (2013).
Ables, G. P., Perrone, C. E., Orentreich, D. & Orentreich, N. Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density. PLOS ONE 7, e51357 (2012). This study and related work show the effects of methionine restriction on glucose metabolism and weight control.
Ables, G. P. et al. Dietary methionine restriction in mice elicits an adaptive cardiovascular response to hyperhomocysteinemia. Sci. Rep. 5, 8886 (2015).
Malloy, V. L. et al. Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Aging Cell 5, 305–314 (2006).
Richie, J. P. Jr. et al. Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J. 8, 1302–1307 (1994).
Caro, P. et al. Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver. Biogerontology 9, 183–196 (2008).
Hasek, B. E. et al. Remodeling the integration of lipid metabolism between liver and adipose tissue by dietary methionine restriction in rats. Diabetes 62, 3362–3372 (2013).
Hasek, B. E. et al. Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R728–R739 (2010).
Anthony, T. G., Morrison, C. D. & Gettys, T. W. Remodeling of lipid metabolism by dietary restriction of essential amino acids. Diabetes 62, 2635–2644 (2013).
Lees, E. K. et al. Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. Aging Cell 13, 817–827 (2014).
Perrone, C. E. et al. Methionine restriction effects on 11 -HSD1 activity and lipogenic/lipolytic balance in F344 rat adipose tissue. J. Lipid Res. 49, 12–23 (2008).
Perrone, C. E., Mattocks, D. A., Jarvis-Morar, M., Plummer, J. D. & Orentreich, N. Methionine restriction effects on mitochondrial biogenesis and aerobic capacity in white adipose tissue, liver, and skeletal muscle of F344 rats. Metabolism 59, 1000–1011 (2010).
Nichenametla, S. N., Mattocks, D. A. L., Malloy, V. L. & Pinto, J. T. Sulfur amino acid restriction-induced changes in redox-sensitive proteins are associated with slow protein synthesis rates. Ann. NY Acad. Sci. 1418, 80–94 (2018).
Castano-Martinez, T. et al. Methionine restriction prevents onset of type 2 diabetes in NZO mice. FASEB J. 33, 7092–7102 (2019).
Yu, D. et al. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J. 32, 3471–3482 (2018).
Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572–583 (2013).
Luckerath, K. et al. 11C-Methionine-PET: a novel and sensitive tool for monitoring of early response to treatment in multiple myeloma. Oncotarget 6, 8418–8429 (2015).
Glaudemans, A. W. et al. Value of 11C-methionine PET in imaging brain tumours and metastases. Eur. J. Nucl. Med. Mol. Imaging 40, 615–635 (2013).
Newman, A. C. & Maddocks, O. D. K. One-carbon metabolism in cancer. Br. J. Cancer 116, 1499–1504 (2017).
Wang, Z. et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat. Med. 25, 825-837 (2019). This study shows a role for methionine metabolism in maintaining tumour-populating cells.
Ulanovskaya, O. A., Zuhl, A. M. & Cravatt, B. F. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat. Chem. Biol. 9, 300–306 (2013).
Eckert, M. A. et al. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature 569, 723–728 (2019).
Kraus, D. et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508, 258–262 (2014).
Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Behrmann, I. et al. Characterization of methylthioadenosin phosphorylase (MTAP) expression in malignant melanoma. Am. J. Pathol. 163, 683–690 (2003).
Illei, P. B., Ladanyi, M., Rusch, V. W. & Zakowski, M. F. The use of CDKN2A deletion as a diagnostic marker for malignant mesothelioma in body cavity effusions. Cancer 99, 51–56 (2003).
Subhi, A. L. et al. Methylthioadenosine phosphorylase regulates ornithine decarboxylase by production of downstream metabolites. J. Biol. Chem. 278, 49868–49873 (2003).
Zhang, H., Chen, Z. H. & Savarese, T. M. Codeletion of the genes for p16INK4, methylthioadenosine phosphorylase, interferon-alpha1, interferon-beta1, and other 9p21 markers in human malignant cell lines. Cancer Genet. Cytogenet. 86, 22–28 (1996).
Ishii, N. et al. Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol. 9, 469–479 (1999).
Hellerbrand, C. et al. Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma. Carcinogenesis 27, 64–72 (2006).
Schmid, M. et al. Homozygous deletions of methylthioadenosine phosphorylase (MTAP) are more frequent than p16INK4A (CDKN2) homozygous deletions in primary non-small cell lung cancers (NSCLC). Oncogene 17, 2669–2675 (1998).
Christopher, S. A., Diegelman, P., Porter, C. W. & Kruger, W. D. Methylthioadenosine phosphorylase, a gene frequently codeleted with p16(cdkN2a/ARF), acts as a tumor suppressor in a breast cancer cell line. Cancer Res. 62, 6639–6644 (2002).
Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218 (2016).
Marjon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 15, 574–587 (2016).
Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351, 1208–1213 (2016).
Chen, Z. H., Olopade, O. I. & Savarese, T. M. Expression of methylthioadenosine phosphorylase cDNA in p16-, MTAP- malignant cells: restoration of methylthioadenosine phosphorylase-dependent salvage pathways and alterations of sensitivity to inhibitors of purine de novo synthesis. Mol. Pharmacol. 52, 903–911 (1997).
Li, W. et al. Status of methylthioadenosine phosphorylase and its impact on cellular response to L-alanosine and methylmercaptopurine riboside in human soft tissue sarcoma cells. Oncol. Res. 14, 373–379 (2004).
Hori, H. et al. Methylthioadenosine phosphorylase cDNA transfection alters sensitivity to depletion of purine and methionine in A549 lung cancer cells. Cancer Res. 56, 5653–5658 (1996).
Chung, J., Karkhanis, V., Baiocchi, R. A. & Sif, S. Protein arginine methyltransferase 5 (PRMT5) promotes survival of lymphoma cells via activation of WNT/beta-CATENIN and AKT/GSK3beta proliferative signaling. J. Biol. Chem. 294, 7692–7710 (2019).
Amano, Y. et al. Expression of protein arginine methyltransferase-5 in oral squamous cell carcinoma and its significance in epithelial-to-mesenchymal transition. Pathol. Int. 68, 359–366 (2018).
Serio, J. et al. The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia. Oncogene 37, 450–460 (2018).
Davidson, S. M. et al. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab. 23, 517–528 (2016).
Mayers, J. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016).
Sanderson, S. M., Mikhael, P. G., Ramesh, V., Dai, Z. & Locasale, J. W. Nutrient availability shapes methionine metabolism in p16/MTAP-deleted cells. Sci. Adv. 5, eaav7769 (2019). This study quantifies the roles of MTAP status and nutrient availability in methionine metabolism.
Mentch, S. J. et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22, 861–873 (2015). The article and related work define biochemical and physiological links of dietary methionine with chromatin state.
Pohjanpelto, P. Putrescine transport is greatly increased in human fibroblasts initiated to proliferate. J. Cell Biol. 68, 512–520 (1976).
Mohan, R. R. et al. Overexpression of ornithine decarboxylase in prostate cancer and prostatic fluid in humans. Clin. Cancer Res. 5, 143–147 (1999).
Hoshino, Y. et al. Ornithine decarboxylase activity as a prognostic marker for colorectal cancer. Fukushima J. Med. Sci. 53, 1–9 (2007).
Deng, W. et al. Role of ornithine decarboxylase in breast cancer. Acta Biochim. Biophys. Sin. 40, 235–243 (2008).
He, W. et al. Targeting ornithine decarboxylase (ODC) inhibits esophageal squamous cell carcinoma progression. NPJ Precis. Oncol. 1, 13 (2017).
O’Brien, T. G., Megosh, L. C., Gilliard, G. & Soler, A. P. Ornithine decarboxylase overexpression is a sufficient condition for tumor promotion in mouse skin. Cancer Res. 57, 2630–2637 (1997).
Dai, F. et al. Extracellular polyamines-induced proliferation and migration of cancer cells by ODC, SSAT, and Akt1-mediated pathway. Anticancer Drugs 28, 457–464 (2017).
Koseki, J. et al. A Trans-omics mathematical analysis reveals novel functions of the ornithine metabolic pathway in cancer stem cells. Sci. Rep. 6, 20726 (2016).
Hayashi, K. et al. Visualization and characterization of cancer stem-like cells in cervical cancer. Int. J. Oncol. 45, 2468–2474 (2014).
Adikrisna, R. et al. Identification of pancreatic cancer stem cells and selective toxicity of chemotherapeutic agents. Gastroenterology 143, 234–245 e237 (2012).
Subhi, A. L. et al. Loss of methylthioadenosine phosphorylase and elevated ornithine decarboxylase is common in pancreatic cancer. Clin. Cancer Res. 10, 7290–7296 (2004).
Scuoppo, C. et al. A tumour suppressor network relying on the polyamine-hypusine axis. Nature 487, 244–248 (2012).
Zabala-Letona, A. et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547, 109–113 (2017). This paper defines a molecular link from mTORC1 signalling to polyamine metabolism that places this pathway in a larger growth control network.
Feinberg, A. P. & Fallin, M. D. Epigenetics at the crossroads of genes and the environment. JAMA 314, 1129–1130 (2015).
Kudo, M., Ikeda, S., Sugimoto, M. & Kume, S. Methionine-dependent histone methylation at developmentally important gene loci in mouse preimplantation embryos. J. Nutr. Biochem. 26, 1664–1669 (2015).
Zhang, N. Role of methionine on epigenetic modification of DNA methylation and gene expression in animals. Anim. Nutr. 4, 11–16 (2018).
Teixeira, V. H. et al. Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions. Nat. Med. 25, 517–525 (2019).
Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, eaal2380 (2017).
Gao, X., Reid, M. A., Kong, M. & Locasale, J. W. Metabolic interactions with cancer epigenetics. Mol. Aspects Med. 54, 50–57 (2017).
Razin, A. & Cedar, H. DNA methylation and gene expression. Microbiol. Rev. 55, 451–458 (1991).
Zhang, W., Spector, T. D., Deloukas, P., Bell, J. T. & Engelhardt, B. E. Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements. Genome Biol. 16, 14 (2015).
Mehrmohamadi, M., Mentch, L. K., Clark, A. G. & Locasale, J. W. Integrative modelling of tumour DNA methylation quantifies the contribution of metabolism. Nat. Commun. 7, 13666 (2016).
Waterland, R. A. Assessing the effects of high methionine intake on DNA methylation. J. Nutr. 136, 1706S–1710S (2006).
Tehlivets, O., Malanovic, N., Visram, M., Pavkov-Keller, T. & Keller, W. S-adenosyl-L-homocysteine hydrolase and methylation disorders: yeast as a model system. Biochim. Biophys. Acta 1832, 204–215 (2013).
Miousse, I. R. et al. Short-term dietary methionine supplementation affects one-carbon metabolism and DNA methylation in the mouse gut and leads to altered microbiome profiles, barrier function, gene expression and histomorphology. Genes Nutr. 12, 22 (2017).
Sinclair, K. D. et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc. Natl Acad. Sci. USA 104, 19351–19356 (2007).
Mattocks, D. A. et al. Short term methionine restriction increases hepatic global DNA methylation in adult but not young male C57BL/6J mice. Exp. Gerontol. 88, 1–8 (2017).
Deblois, G. et al. Metabolic adaptations underlie epigenetic vulnerabilities in chemoresistant breast cancer. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/286054v2 (2018). This study defines a role for methionine metabolism in mediating chemotherapy resistance.
Shima, H. et al. S-adenosylmethionine synthesis is regulated by selective N(6)-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1. Cell Rep. 21, 3354–3363 (2017). This study defines a link from methionine metabolism to RNA (m6A) methylation.
Pendleton, K. E. et al. The U6 snRNA m(6)A methyltransferase METTL16 regulates SAM synthetase intron retention. Cell 169, 824–835 e814 (2017).
Laxman, S. et al. Sulfur amino acids regulate translational capacity and metabolic homeostasis through modulation of tRNA thiolation. Cell 154, 416–429 (2013).
Maddocks, O. D., Labuschagne, C. F., Adams, P. D. & Vousden, K. H. Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol. Cell 61, 210–221 (2016).
Mentch, S. J. & Locasale, J. W. One-carbon metabolism and epigenetics: understanding the specificity. Ann. N Y Acad Sci. 1363, 91–98 (2016).
Dai, Z., Mentch, S. J., Gao, X., Nichenametla, S. N. & Locasale, J. W. Methionine metabolism influences genomic architecture and gene expression through H3K4me3 peak width. Nat. Commun. 9, 1955 (2018). This paper investigates how methionine levels link to specific features of the genomic architecture.
Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).
Kondo, Y. et al. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat. Genet. 40, 741–750 (2008).
Pan, M. et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18, 1090–1101 (2016).
Kinnaird, A., Zhao, S., Wellen, K. E. & Michelakis, E. D. Metabolic control of epigenetics in cancer. Nat. Rev. Cancer 16, 694–707 (2016).
Shiraki, N. et al. Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab. 19, 780–794 (2014).
Ding, W. et al. s-Adenosylmethionine levels govern innate immunity through distinct methylation-dependent pathways. Cell Metab. 22, 633–645 (2015). This study shows that methionine may play a role in innate immunity through chromatin.
Tang, S. et al. Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development. EMBO J. 36, 3175–3193 (2017).
Jakubowski, H. Homocysteine thiolactone: metabolic origin and protein homocysteinylation in humans. J. Nutr. 130, 377S–381S (2000).
Seshadri, S. et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J. Med. 346, 476–483 (2002).
Den Heijer, M., Lewington, S. & Clarke, R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J. Thromb Haemost 3, 292–299 (2005).
Chwatko, G., Boers, G. H., Strauss, K. A., Shih, D. M. & Jakubowski, H. Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice. FASEB J. 21, 1707–1713 (2007).
Zhang, Q. et al. Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects. Nat. Commun. 9, 3436 (2018).
Stone, K. P., Wanders, D., Orgeron, M., Cortez, C. C. & Gettys, T. W. Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice. Diabetes 63, 3721–3733 (2014).
Sugimura, T., Birnbaum, S. M., Winitz, M. & Greenstein, J. P. Quantitative nutritional studies with water-soluble, chemically defined diets. VII. Nitrogen balance in normal and tumor-bearing rats following forced feeding. Arch Biochem Biophys 81, 439–447 (1959).
Guo, H. et al. Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo. Cancer Res. 53, 5676–5679 (1993).
Poirson-Bichat, F. et al. Methionine deprivation and methionine analogs inhibit cell proliferation and growth of human xenografted gliomas. Life Sci. 60, 919–931 (1997).
Poirson-Bichat, F., Goncalves, R. A., Miccoli, L., Dutrillaux, B. & Poupon, M. F. Methionine depletion enhances the antitumoral efficacy of cytotoxic agents in drug-resistant human tumor xenografts. Clin. Cancer Res. 6, 643–653 (2000).
Goseki, N. et al. Antitumor effect of methionine-depleting total parenteral nutrition with doxorubicin administration on Yoshida sarcoma-bearing rats. Cancer 69, 1865–1872 (1992).
Strekalova, E., Malin, D., Good, D. M. & Cryns, V. L. Methionine deprivation induces a targetable vulnerability in triple-negative breast cancer cells by enhancing TRAIL Receptor-2 expression. Clin. Cancer Res. 21, 2780–2791 (2015).
Jeon, H. et al. Methionine deprivation suppresses triple-negative breast cancer metastasis in vitro and in vivo. Oncotarget 7, 67223–67234 (2016).
Plaisance, E. P. et al. Dietary methionine restriction increases fat oxidation in obese adults with metabolic syndrome. J. Clin. Endocrinol Metab. 96, E836–E840 (2011).
Gao, X. et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature https://doi.org/10.1038/s41586-019-1437-3 (2019).
Moding, E. J. et al. ATM deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium. J. Clin. Invest 124, 3325–3338 (2014).
Agrawal, V., Alpini, S. E., Stone, E. M., Frenkel, E. P. & Frankel, A. E. Targeting methionine auxotrophy in cancer: discovery & exploration. Expert Opin Biol. Ther 12, 53–61 (2012).
Hoffman, R. M. & Erbe, R. W. High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine. Proc Natl Acad Sci. U S A 73, 1523–1527 (1976).
Judde, J. G., Ellis, M. & Frost, P. Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells. Cancer Res. 49, 4859–4865 (1989).
Wanders, D. et al. Role of GCN2-independent signaling through a noncanonical PERK/NRF2 pathway in the physiological responses to dietary methionine restriction. Diabetes 65, 1499–1510 (2016).
Wanders, D. et al. FGF21 mediates the thermogenic and insulin-sensitizing effects of dietary methionine restriction but not its effects on hepatic lipid metabolism. Diabetes 66, 858–867 (2017).
Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017). This study defines a novel biochemical SAM-sensing mechanism through direct interaction with mTORC1.
Hine, C. et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160, 132–144 (2015).
Lien, E. C., Ghisolfi, L., Geck, R. C., Asara, J. M. & Toker, A. Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT. Sci. Signal. 10, eaao6604 (2017).
Visentin, M., Zhao, R. & Goldman, I. D. The antifolates. Hematol Oncol. Clin. North Am. 26, 629–648, ix (2012).
Poirson-Bichat, F., Gonfalone, G., Bras-Goncalves, R. A., Dutrillaux, B. & Poupon, M. F. Growth of methionine-dependent human prostate cancer (PC-3) is inhibited by ethionine combined with methionine starvation. Br. J. Cancer 75, 1605–1612 (1997).
Kreis, W. & Hession, C. Isolation and purification of L-methionine-alpha-deamino-gamma-mercaptomethane-lyase (L-methioninase) from Clostridium sporogenes. Cancer Res. 33, 1862–1865 (1973).
Tan, Y., Zavala, J., Sr, Xu, M., Zavala, J. Jr. & Hoffman, R. M. Serum methionine depletion without side effects by methioninase in metastatic breast cancer patients. Anticancer Res. 16, 3937–3942 (1996).
Tan, Y. et al. Recombinant methioninase infusion reduces the biochemical endpoint of serum methionine with minimal toxicity in high-stage cancer patients. Anticancer Res. 17, 3857–3860 (1997).
Kawaguchi, K. et al. Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models. Oncotarget 9, 915–923 (2018).
Murakami, T. et al. Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8, 35630–35638 (2017).
Igarashi, K. et al. Effective metabolic targeting of human osteosarcoma cells in vitro and in orthotopic nude-mouse models with recombinant methioninase. Anticancer Res. 37, 4807–4812 (2017).
Hoffman, R. M. et al. Pilot Phase I clinical trial of methioninase on high-stage cancer patients: rapid depletion of circulating methionine. Methods Mol. Biol. 1866, 231–242 (2019).
Lubin, M. & Lubin, A. Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy. PLOS ONE 4, e5735 (2009).
Tang, B., Lee, H. O., An, S. S., Cai, K. Q. & Kruger, W. D. Specific targeting of MTAP-deleted tumors with a combination of 2’-fluoroadenine and 5’-methylthioadenosine. Cancer Res. 78, 4386–4395 (2018).
Kindler, H. L., Burris, H. A. 3rd, Sandler, A. B. & Oliff, I. A. A phase II multicenter study of L-alanosine, a potent inhibitor of adenine biosynthesis, in patients with MTAP-deficient cancer. Invest. New Drugs 27, 75–81 (2009).
Targeting MAT2A in MTAP-deleted cancers. Agios. http://investor.agios.com/static-files/6f86f736-a23c-4c9c-b455-81c1ac1128f9 (2018).
Metcalf, B. W. et al. Catalytic irreversible inhibition of mammalian ornithine decarboxylase (E.C.22.214.171.124) by substrate and product analogs. J. Am. Chem. Soc. 100, 2551–2553 (1978).
Luk, G. D., Civin, C. I., Weissman, R. M. & Baylin, S. B. Ornithine decarboxylase: essential in proliferation but not differentiation of human promyelocytic leukemia cells. Science 216, 75–77 (1982).
Meyskens, F. L., Kingsley, E. M., Glattke, T., Loescher, L. & Booth, A. A phase II study of alpha-difluoromethylornithine (DFMO) for the treatment of metastatic melanoma. Invest. New Drugs 4, 257–262 (1986).
Abeloff, M. D. et al. Phase II trials of alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, in advanced small cell lung cancer and colon cancer. Cancer Treat. Rep. 70, 843–845 (1986).
Seiler, N., Delcros, J. G. & Moulinoux, J. P. Polyamine transport in mammalian cells. An update. Int. J. Biochem. Cell Biol. 28, 843–861 (1996).
Sholler, G. L. S. et al. Maintenance DFMO increases survival in high risk neuroblastoma. Sci. Rep. 8, 14445 (2018).
Hogarty, M. D. et al. ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma. Cancer Res. 68, 9735–9745 (2008).
Wagner, A. J., Meyers, C., Laimins, L. A. & Hay, N. c-Myc induces the expression and activity of ornithine decarboxylase. Cell Growth Differ. 4, 879–883 (1993).
Hayes, C. S. et al. Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol. Res. 2, 274–285 (2014).
Tang, B., Kadariya, Y., Chen, Y., Slifker, M. & Kruger, W. D. Expression of MTAP inhibits tumor-related phenotypes in HT1080 cells via a mechanism unrelated to its enzymatic function. G3 5, 35–44 (2014).
Bai, J. et al. Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes. EBioMedicine 39, 575–590 (2019).
Quinlan, C. L. et al. Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. Nat. Chem. Biol. 13, 785–792 (2017).
Warder, S. E. et al. Discovery, identification, and characterization of candidate pharmacodynamic markers of methionine aminopeptidase-2 inhibition. J. Proteome Res. 7, 4807–4820 (2008).
Burkey, B. F. et al. Preclinical efficacy and safety of the novel antidiabetic, antiobesity MetAP2 inhibitor ZGN-1061. J. Pharmacol. Exp. Ther. 365, 301–313 (2018).
Jones, P. A., Issa, J. P. & Baylin, S. Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17, 630–641 (2016).
Chaturvedi, P., Kamat, P. K., Kalani, A., Familtseva, A. & Tyagi, S. C. High methionine diet poses cardiac threat: a molecular insight. J. Cell Physiol. 231, 1554–1561 (2016).
McCampbell, A. et al. Induction of Alzheimer’s-like changes in brain of mice expressing mutant APP fed excess methionine. J. Neurochem. 116, 82–92 (2011).
Weaver, I. C. et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J. Neurosci. 25, 11045–11054 (2005).
Sinclair, L. V. et al. Antigen receptor control of methionine metabolism in T cells. eLife 8, e44210 (2019).
Durando, X. et al. Optimal methionine-free diet duration for nitrourea treatment: a Phase I clinical trial. Nutr. Cancer 60, 23–30 (2008).
Durando, X. et al. Dietary methionine restriction with FOLFOX regimen as first line therapy of metastatic colorectal cancer: a feasibility study. Oncology 78, 205–209 (2010).
Epner, D. E., Morrow, S., Wilcox, M. & Houghton, J. L. Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase I clinical trial of dietary methionine restriction. Nutr. Cancer 42, 158–166 (2002).
Thivat, E. et al. Phase II trial of the association of a methionine-free diet with cystemustine therapy in melanoma and glioma. Anticancer Res. 29, 5235–5240 (2009).
Maddocks, O. D. K. et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544, 372–376 (2017).
Pegg, A. E. Functions of polyamines in mammals. J. Biol. Chem. 291, 14904–14912 (2016).
Ye, C., Sutter, B. M., Wang, Y., Kuang, Z. & Tu, B. P. A metabolic function for phospholipid and histone methylation. Mol. Cell 66, 180–193.e188 (2017).
Hosios, A. M. & Vander Heiden, M. G. The redox requirements of proliferating mammalian cells. J. Biol. Chem. 293, 7490–7498 (2018).
Sutter, B. M., Wu, X., Laxman, S. & Tu, B. P. Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A. Cell 154, 403–415 (2013).
Mazor, K. M. et al. Effects of single amino acid deficiency on mRNA translation are markedly different for methionine versus leucine. Sci. Rep. 8, 8076 (2018).
Ogawa, T. et al. Stimulating S-adenosyl-l-methionine synthesis extends lifespan via activation of AMPK. Proc. Natl Acad. Sci. USA 113, 11913–11918 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03435250?term=ag270&rank=1 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03614728?term=gsk3326595&rank=1 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03854227?term=pf06939999&rank=1 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03573310?term=jnj64619178&rank=1 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02030964?term=topotecan+dfmo&rank=1 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03536728?term=amxt&rank=1 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03138538?term=m8891&rank=1 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03744793?term=mtap+pemetrexed&rank=1 (2019).
We thank numerous colleagues over the years who have helped shape our thoughts on methionine metabolism, particularly those at the Orentreich Foundation for the Advancement of Science.
The authors have no competing interests to declare at this time.
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US Department of Agriculture Food Composition Database: https://ndb.nal.usda.gov/ndb/
- Dietary methionine restriction
(MR). A diet characterized by reduced methionine levels compared to a standard reference diet; the degree of restriction can vary between studies.
Genetic predisposition that causes subjects to exhibit advanced physiological ageing.
(SAM). Methionine-derived universal methyl donor required for all cellular methylation reactions.
- One-carbon metabolism
Set of biochemical reactions that allow for the transfer of single carbon units from dietary nutrients, particularly amino acids, in order to fuel critical cellular processes.
Methionine-derived polycations that interact with negatively charged moieties of DNA and other proteins and lipids.
- Methylthioadenosine phosphorylase
(MTAP). Enzyme involved in the salvage of methionine and adenine from by-products of polyamine biosynthesis.
Biochemical addition of a methyl group (composed of one carbon and three hydrogen atoms, or CH3) to another substrate.
- Methionine adenosyltransferase 2A
(MAT2A). Enzyme that catalyses the ATP-dependent conversion of methionine to SAM.
- Protein arginine N-methyltransferase 5
(PRMT5). Methyltransferase that catalyses the monomethylation and symmetrical dimethylation of arginine residues of proteins.
- Collateral vulnerabilities
Co-deletion of a gene proximal to a tumour suppressor gene, resulting in a targetable vulnerability independent of the tumour suppressor deletion.
- Ornithine decarboxylase
(ODC). Enzyme that catalyses the conversion of ornithine to putrescine, the initial and committing step of polyamine biosynthesis.
- Adenosylmethionine decarboxylase 1
(AMD1). Enzyme responsible for the decarboxylation of SAM for polyamine biosynthesis.
DNA-interacting proteins responsible for organizing DNA into structural units called nucleosomes.
Addition of a thiol-containing homocysteine molecule to proteins via acylation of a lysine residue.
- Age-related disorders
Physiological states or diseases (including metabolic, neurological or other types) whose incidence is more prevalent in ageing populations.
- Dietary methionine depletion
A diet characterized by total removal of methionine.
- Walker-256 carcinosarcoma
A rat-derived transplantable carcinosarcoma cell line; tends to exhibit carcinoma characteristics when transplanted in younger rats, and sarcoma characteristics in older rats.
- Yoshida sarcoma
A transplantable allograft sarcoma tumour model derived from ascites; one of the first cancer cell lines successfully generated.
Systematic identification and quantification of metabolic products (metabolites).
- Sulfur metabolism
Biological processes involving methionine and cysteine.
- Patient-derived xenograft
(PDX). Preclinical cancer model whereby patient-excised tumour cells are directly implanted into immunodeficient mice.
(5-FU). A pyrimidine analogue that inhibits nucleotide synthesis, functioning as an antimetabolite chemotherapy.
- Gene–environment interactions
Relationships through which genetic status influences how a given cell/organism responds to environmental variation.
- Methionine aminopeptidase 2
(MetAP2). Metallopeptidase responsible for removing N-terminal methionine residues from newly translated proteins.
A chloroethylnitrosourea chemotherapy agent approved for the treatment of high-grade melanomas and gliomas.
- Precision diets
Systematic development of personalized diets; can be individual-specific or more broadly orientated towards a particular nutrient or disease.
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Sanderson, S.M., Gao, X., Dai, Z. et al. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer 19, 625–637 (2019). https://doi.org/10.1038/s41568-019-0187-8
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