Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press72810.17650/2313-805X-2024-11-4-41-53REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИThe role of methionine cycle disruption in the initiation and progression of malignant tumorsРоль нарушения цикла метионина в инициации и прогрессии злокачественных опухолейhttps://orcid.org/0000-0001-8142-4283RukshaT. G.РукшаТ. Г.
Russian Federation

Tatiana Gennadievna Ruksha

1 Partizanа Zheleznyakа St., Krasnoyarsk 660022

Татьяна Геннадьевна Рукша

660022 Красноярск, ул. Партизана Железняка, 1

tatyana_ruksha@mail.ruhttps://orcid.org/0000-0002-8518-2450KurbatM. N.КурбатМ. Н.
Belarus

80 Gorkogo St., Grodno 230009

230009 Гродно, ул. Горького, 80

https://orcid.org/0000-0002-6801-3452PalkinaN. V.ПалкинаН. В.
Russian Federation

1 Partizanа Zheleznyakа St., Krasnoyarsk 660022

660022 Красноярск, ул. Партизана Железняка, 1

KutsenkoV. A.КуценкоВ. А.
Russian Federation

1 Partizanа Zheleznyakа St., Krasnoyarsk 660022

660022 Красноярск, ул. Партизана Железняка, 1

Prof. V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Ministry of Health of RussiaФГБОУ ВО «Красноярский государственный медицинский университет им. проф. В.Ф. Войно-Ясенецкого» Минздрава РоссииGrodno State Medical UniversityУО «Гродненский государственный медицинский университет1512202411441530912202409122024Copyright ©; 2024, Ruksha T.G., Kurbat M.N., Palkina N.V., Kutsenko V.A.Copyright ©; 2024, Рукша Т.Г., Курбат М.Н., Палкина Н.В., Куценко В.А.2024Ruksha T.G., Kurbat M.N., Palkina N.V., Kutsenko V.A.Рукша Т.Г., Курбат М.Н., Палкина Н.В., Куценко В.А.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/728

The methionine cycle is responsible for the metabolism of substances associated with methionine, one of the essential amino acids for protein synthesis. The methionine cycle dysregulation leads to non-proteinogenic amino acid homocysteine accumulation that can have a negative impact on a health. Numerous studies describe homocysteine effect on cardiovascular pathology development but its role in carcinogenesis remains poorly understood. Therefore, the purpose of this review is to analyze scientific data regarding the role of methionine catabolism dysregulation in a cell neoplastic transformation and tumor growth. Understanding cellular alterations of methionine metabolism is important for novel anti-cancer drugs development as well as establishing approaches for combinatorial treatment strategies aiming to overcome metabolic plasticity of cancer cells and their drug resistance.

Метиониновый цикл отвечает за обмен веществ, связанных с метионином – одним из незаменимых аминокислотных компонентов белков. при нарушении регуляции этого процесса происходит накопление непротеиногенной аминокислоты гомоцистеина, что может негативно влиять на организм человека. Существует множество исследований, посвященных изучению воздействия данных нарушений на развитие болезней системы кровообращения, однако их роль в развитии злокачественных новообразований остается малоизученной. Цель обзора – проанализировать научные работы, в которых рассматривается влияние сбоя регуляции метионинового катаболизма на возникновение и прогрессирование опухолевого роста. Понимание метаболических изменений, связанных с канцерогенезом, имеет большое значение для разработки новых классов терапевтических препаратов, а также стратегий комбинированного противоопухолевого лечения, в том числе направленных на преодоление метаболических особенностей опухолевых клеток.

methioninehomocysteinecarcinogenesistumor progressionchemotherapyметионингомоцистеинканцерогенезопухолевая прогрессияхимиотерапияKim S., Fenech M.F., Kim P.J. Nutritionally recommended food for semi-to strict vegetarian diets based on large-scale nutrient composition data. Sci Rep 2018;8(1):4344. DOI: 10.1038/s41598-018-22691-1Jubinville É., Milad N., Maranda-Robitaille M. et al. Critical importance of dietary methionine and choline in the maintenance of lung homeostasis during normal and cigarette smoke exposure conditions. Am J Physiol Lung Cell Mol Physiol 2021;319(2):L391–402. DOI: 10.1152/ajplung.00353.2019Sanderson S.M., Gao X., Dai Z., Locasale J.W. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer. 2019;19(11):625–37. DOI: 10.1038/s41568-019-0187-8Li Z., Wang F., Liang B. et al. Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication. Signal Transduct Target Ther 2020;5(1):280. DOI: 10.1038/s41392-020-00349-7Austin R.C., Lentz S.R., Werstuck G.H. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 2004;11(1):S56–64. DOI: 10.1038/sj.cdd.4401451Pokrovsky V.S., Abo Kura L., Demidova E.A. et al. Methionine dependence of cancer cells is a target of methioninase. Biokhimiya = Biochemistry 2023;88(7):1162–72. (In Russ.). DOI: 10.31857/S0320972523070072Покровский В.С., Або Кура Л., Демидова Е.А. и др. Метиониновая зависимость раковых клеток – мишень метиониназы. Биохимия 2023;88(7):1162–72. DOI: 10.31857/S0320972523070072Muñoz-Esparza N.C., Latorre-Moratalla M.L., Comas-Basté O. et al. Polyamines in food. Front Nutr 2019;6:108. DOI: 10.3389/fnut.2019.00108Mendoza J., Purchal M., Yamada K., Koutmos M. Structure of full-length cobalamin-dependent methionine synthase and cofactor loading captured in crystallo. Nat Commun 2023;14(1):6365. DOI: 10.1038/s41467-023-42037-4Blake G.E.T., Zhao X., Yung H.W. et al. Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker. Nat Commun 2021;12(1):3714. DOI: 10.1038/s41467-021-24036-5Suthandiram S., Gan G.G., Zain S.M. et al. Polymorphisms in methylenetetrahydrofolate reductase gene and risk of non-Hodgkin lymphoma in a multi-ethnic population. J Hum Genet 2014;59(5):280–7. DOI: 10.1038/jhg.2014.19Wan L., Li Y., Zhang Z. et al. Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry 2018;8(1):242. DOI: 10.1038/s41398-018-0276-6Reeves S.G., Meldrum C., Groombridge C. et al. MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer. Eur J Hum Genet 2009;17(5):629–35. DOI: 10.1038/ejhg.2008.239Poursalehi D., Lotfi K., Mirzaei S. et al. Association between methyl donor nutrients and metabolic health status in overweight and obese adolescents. Sci Rep 2022;12(1):17045. DOI: 10.1038/s41598-022-21602-9Tseimakh I.Ya., Kostyuchenko G.I., Bogachev D.E. Effect of folic acid in patients with lung damage caused by coronavirus SARS-CoV-2. Sibirskoe meditsinskoe obozrenie = Siberian Medical Review 2021;(6):60–9. (In Russ.). DOI: 10.20333/25000136-2021-6-60-69Цеймах И.Я., Костюченко Г.И., Богачев Д.Е. и др. Эффекты фолиевой кислоты у больных с поражением легких, вызванным коронавирусом SARS-CoV-2. Сибирское медицинское обозрение 2021;(6):60–9. DOI: 10.20333/25000136-2021-6-60-69Xue Y., Lu F., Chang Z. et al. Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade. Nat Commun 2023;14(1):4758. DOI: 10.1038/s41467-023-40518-0Durand P., Prost M., Loreau N. et al. Impaired homocysteine metabolism and atherothrombotic disease. Lab Invest 2001;81(5):645–72. DOI: 10.1038/labinvest.3780275Hasan T., Arora R., Bansal A.K. et al. Disturbed homocysteine metabolism is associated with cancer. Exp Mol Med 2019;51(2):1–13. DOI: 10.1038/s12276-019-0216-4Lim J.M., Kim G., Levine R.L. Methionine in Proteins: It’s Not Just for Protein Initiation Anymore. Neurochem Res 2019;44(1):247–57. DOI: 10.1007/s11064-017-2460-0Weissbach H., Resnick L., Brot N. Methionine sulfoxide reductases: history and cellular role in protecting against oxidative damage. Biochim Biophys Acta 2005;1703(2):203–12. DOI: 10.1016/j.bbapap.2004.10.004Ohno M., Takano N., Hidaka K. et al. Oxidative stress accelerates intestinal tumorigenesis by enhancing 8-oxoguanine-mediated mutagenesis in MUTYH-deficient mice. Genome Res 2024;34(1):47–56. DOI: 10.1101/gr.278326.123Milligan J.R., Aguilera J.A., Ly A. et al. Repair of oxidative DNA damage by amino acids. Nucleic Acids Res 2003;31(21):6258–63. DOI: 10.1093/nar/gkg816Zhang L., Xu R., Ma X. et al. Mechanism of arterial injury exacerbated by hyperhomocysteinemia in spontaneously hypertensive rats. Sci Rep 2023;13(1):2482. DOI: 10.1038/s41598-023-28731-9Lubos E., Loscalzo J., Handy D.E. Homocysteine and glutathione peroxidase-1. Antioxid Redox Signal 2007;9(11):1923–40. DOI: 10.1089/ars.2007.1771Zeng X.K., Guan Y.F., Remick D.G., Wang X. Signal pathways underlying homocysteine-induced production of MCP-1 and IL-8 in cultured human whole blood. Acta Pharmacol Sin 2005;26(1):85–91. DOI: 10.1111/j.1745-7254.2005.00005.xVillalobo A., Berchtold M.W. The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis. Int J Mol Sci 2020;21(3):765. PMID: 31991573. DOI: 10.3390/ijms21030765You M., Xie Z., Zhang N. et al. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Signal Transduct Target Ther 2023;8(1):196. DOI: 10.1038/s41392-023-01442-3Kadam M.S., Burra V.L.S.P. S-adenosyl-l-methionine interaction signatures in methyltransferases. J Biomol Struct Dyn 2024;42(6):3166–76. DOI: 10.1080/07391102.2023.2217679Wu Y.L., Lin Z.J., Li C.C. et al. Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study. Signal Transduct Target Ther 2023;8(1):98. DOI: 10.1038/s41392-023-01333-7Moore L.D., Le T., Fan G. DNA methylation and its basic function. Neuropsychopharmacology 2013;38(1):23–38. DOI: 10.1038/npp.2012.112Luo J., Li Y.N., Wang F. et al. S-adenosylmethionine inhibits the growth of cancer cells by reversing the hypomethylation status of c-myc and H-ras in human gastric cancer and colon cancer. Int J Biol Sci 2010;6(7):784–95. DOI: 10.7150/ijbs.6.784Kong Y., Rose C.M., Cass A.A. et al. Transposable element expression in tumors is associated with immune infiltration and increased antigenicity. Nat Commun 2019;10(1):5228. DOI: 10.1038/s41467-019-13035-2Shah A.H., Govindarajan V., Doucet-O’Hare T.T. et al. Differential expression of an endogenous retroviral element [HERV-K(HML-6)] is associated with reduced survival in glioblastoma patients. Sci Rep 2022;12(1):6902. DOI: 10.1038/s41598-022-10914-5Van Tongelen A., Loriot A., De Smet C. Oncogenic roles of DNA hypomethylation through the activation of cancer-germline genes. Cancer Lett 2017;396:130–7. DOI: 10.1016/j.canlet.2017.03.029Li G., Li D., Wu C. et al. Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9. Exp Mol Med 2022;54(7):988–98. DOI: 10.1038/s12276-022-00804-1Erichsen L., Ghanjati F., Beermann A. et al. Aberrant methylated key genes of methyl group metabolism within the molecular etiology of urothelial carcinogenesis. Sci Rep 2018;8(1):6051. DOI: 10.1038/s41598-018-23158-zSoltani M., Zhao Y., Xia Z. et al. The importance of cellular metabolic pathways in pathogenesis and selective treatments of hematological malignancies. Front Oncol 2021;11:767026. DOI: 10.3389/fonc.2021.767026Bian Y., Li W., Kremer D.M. et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 2020;585(7824):277–82. DOI: 10.1038/s41586-020-2682-1Stern P.H., Hoffman R.M. Enhanced in vitro selective toxicity of chemotherapeutic agents for human cancer cells based on a metabolic defect. J Natl Cancer Inst 1986;76(4):629–39. DOI: 10.1093/jnci/76.4.629Sedillo J.C., Cryns V.L. Targeting the methionine addiction of cancer. Am J Cancer Res 2022;12(5):2249–76.Wang Z., Yip L.Y., Lee J.H.J. et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 2019;25(5):825–37. PMID: 31061538. DOI: 10.1038/s41591-019-0423-5Yang H.B., Xu Y.Y., Zhao X.N. et al. Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer. Nat Commun 2015;6:6973. DOI: 10.1038/ncomms7973Gao X., Sanderson S.M., Dai Z. et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 2019;572(7769):397–401. DOI: 10.1038/s41586-019-1437-3Lee B.C., Kaya A., Gladyshev V.N. Methionine restriction and life-span control. Ann N Y Acad Sci 2016;1363:116–24. DOI: 10.1111/nyas.12973Abo Qoura L., Balakin K.V., Hoffman R.M., Pokrovsky V.S. The potential of methioninase for cancer treatment. Biochim Biophys Acta Rev Cancer 2024;1879(4):189122. DOI: 10.1016/j.bbcan.2024.189122Lee B.C., Kaya A., Ma S. et al. Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino-acid status. Nat Commun 2014;5:3592. DOI: 10.1038/ncomms4592Fontana L., Weiss E.P., Villareal D.T. et al. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 2008;7(5):681–7. DOI: 10.1111/j.1474-9726.2008.00417.xWang L., Cai H., Hu Y. et al. A pharmacological probe identifies cystathionine β-synthase as a new negative regulator for ferroptosis. Cell Death Dis 2018;9(10):1005. DOI: 10.1038/s41419-018-1063-2Booher K., Lin D.W., Borrego S.L., Kaiser P. Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells. Cell Cycle 2012;11(23):4414–23. DOI: 10.4161/cc.22767Borrego S.L., Lin D.W., Kaiser P. Isolation and characterization of methionine-independent clones from methionine-dependent cancer cells. Methods Mol Biol 2019;1866:37–48. DOI: 10.1007/978-1-4939-8796-2_4Li F., Liu P., Mi W. et al. Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer. Nat Cancer 2024;5(1):131–46. DOI: 10.1038/s43018-023-00671-3Grigorash B.B., van Essen D., Liang G. et al. p16High senescence restricts cellular plasticity during somatic cell reprogramming. Nat Cell Biol 2023;25(9):1265–78. DOI: 10.1038/s41556-023-01214-9Yang C., Ou Y., Zhou Q. et al. Methionine orchestrates the metabolism vulnerability in cisplatin resistant bladder cancer microenvironment. Cell Death Dis 2023;14(8):525. DOI: 10.1038/s41419-023-06050-1Li J.T., Yang H., Lei M.Z. et al. Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA. Signal Transduct Target Ther 2022;7(1):192. DOI: 10.1038/s41392-022-01017-8Yang H., Huang Z.Z., Wang J., Lu S.C. The role of c-Myb and Sp1 in the up-regulation of methionine adenosyltransferase 2A gene expression in human hepatocellular carcinoma. FASEB J 2001;15(9):1507–16. DOI: 10.1096/fj.01-0040comYang H., Sadda M.R., Yu V. et al. Induction of human methionine adenosyltransferase 2A expression by tumor necrosis factor alpha. Role of NF-kappa B and AP-1. J Biol Chem 2003;278(51):50887–96. DOI: 10.1074/jbc.M307600200Strekalova E., Malin D., Weisenhorn E.M.M. et al. S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability of cancer stem cells. Breast Cancer Res Treat 2019;175(1):39–50. DOI: 10.1007/s10549-019-05146-7He D., Feng H., Sundberg B. et al. Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis. Mol Cell 2022;82(16):3045–60.e11. DOI: 10.1016/j.molcel.2022.06.005Roybal C.N., Yang S., Sun C.W. et al. Homocysteine increases the expression of vascular endothelial growth factor by a mechanism involving endoplasmic reticulum stress and transcription factor ATF4. J Biol Chem 2004;279(15):14844–52. DOI: 10.1074/jbc.M312948200Zhao W.X., Liu Z.F., Li X.L., Li Z. Correlations of serum homocysteine, VEGF and gastrin 17 with gastric cancer and precancerous lesions. Eur Rev Med Pharmacol Sci 2019;23(10):4192–8. DOI: 10.26355/eurrev_201905_17922