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Cysteine Metabolism in Cancer Progression and Therapy Resistance

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Abstract

Redox homeostasis and sustainable energy production are vital for cancer survival and growth. As cancer cells proliferate uncontrollably, metabolic substrate dwindles, while reactive chemical species rise. To overcome these challenges, cancer cells evolve to switch to alternative metabolic substrate available and boost its anti-oxidative defense. Emerging studies implicate nonessential amino acid cysteine in these two pro-cancer processes, which in turn promote resistance to therapy. Here, we will discuss the role of cysteine metabolism in cancer progression, focusing on how increased cysteine uptake enables metabolic flexibility and benefits cancer survival. The interplay between cysteine metabolism and other metabolic pathways and the regulation of cysteine homeostasis in cancer and the tumor microenvironment will also be addressed. Finally, we will also discuss current developments in targeting cysteine flux to impede tumor growth and therapy resistance.

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References

  1. Cantor JR, Sabatini DM. Cancer cell metabolism: one hallmark, many faces. Cancer Discov. 2012;2(10):881–98. https://doi.org/10.1158/2159-8290.Cd-12-0345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33. https://doi.org/10.1126/science.1160809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95. https://doi.org/10.1038/nrc2981.

    Article  CAS  PubMed  Google Scholar 

  4. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23(5):537–48. https://doi.org/10.1101/gad.1756509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Choi B-H, Coloff JL. The diverse functions of non-essential amino acids in cancer. Cancers. 2019;11(5) https://doi.org/10.3390/cancers11050675.

  6. Combs JA, DeNicola GM. The non-essential amino acid cysteine becomes essential for tumor proliferation and survival. Cancers. 2019;11(5) https://doi.org/10.3390/cancers11050678.

  7. Koppula P, Zhang Y, Shi J, Li W, Gan B. The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. J Biol Chem. 2017;292(34):14240–9. https://doi.org/10.1074/jbc.M117.798405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu X, Olszewski K, Zhang Y, Lim EW, Shi J, Zhang X, Zhang J, Lee H, Koppula P, Lei G, Zhuang L, You MJ, Fang B, Li W, Metallo CM, Poyurovsky MV, Gan B. Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer. Nat Cell Biol. 2020;22(4):476–86. https://doi.org/10.1038/s41556-020-0496-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Muir A, Danai LV, Gui DY, Waingarten CY, Lewis CA, Vander Heiden MG. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. elife. 2017;6 https://doi.org/10.7554/eLife.27713.

  10. Shin C-S, Mishra P, Watrous JD, Carelli V, D’Aurelio M, Jain M, Chan DC. The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility. Nat Commun. 2017;8(1) https://doi.org/10.1038/ncomms15074.

  11. Stipanuk MH, Dominy JE, Lee J-I, Coloso RM. Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism. J Nutr. 2006;136(6):1652S–9S. https://doi.org/10.1093/jn/136.6.1652S.

    Article  CAS  PubMed  Google Scholar 

  12. Yin J, Ren W, Yang G, Duan J, Huang X, Fang R, Li C, Li T, Yin Y, Hou Y, Kim SW, Wu G. l-cysteine metabolism and its nutritional implications. Mol Nutr Food Res. 2016;60(1):134–46. https://doi.org/10.1002/mnfr.201500031.

    Article  CAS  PubMed  Google Scholar 

  13. Bradley H, Gough A, Sokhi RS, Hassell A, Waring R, Emery P. Sulfate metabolism is abnormal in patients with rheumatoid arthritis. Confirmation by in vivo biochemical findings. J Rheumatol. 1994;21(7):1192–6.

    CAS  PubMed  Google Scholar 

  14. Heafield MT, Fearn S, Steventon GB, Waring RH, Williams AC, Sturman SG. Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson’s and Alzheimer’s disease. Neurosci Lett. 1990;110(1-2):216–20. https://doi.org/10.1016/0304-3940(90)90814-p.

    Article  CAS  PubMed  Google Scholar 

  15. Wu G, Fang Y-Z, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134(3):489–92. https://doi.org/10.1093/jn/134.3.489.

    Article  CAS  PubMed  Google Scholar 

  16. Mandal PK, Seiler A, Perisic T, Kölle P, Banjac Canak A, Förster H, Weiss N, Kremmer E, Lieberman MW, Bannai S, Kuhlencordt P, Sato H, Bornkamm GW, Conrad M. System xc−and thioredoxin reductase 1 cooperatively rescue glutathione deficiency. J Biol Chem. 2010;285(29):22244–53. https://doi.org/10.1074/jbc.M110.121327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vučetić M, Cormerais Y, Parks SK, Pouysségur J. The central role of amino acids in cancer redox homeostasis: vulnerability points of the cancer redox code. Front Oncol. 2017;7 https://doi.org/10.3389/fonc.2017.00319.

  18. Conrad M, Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (−) : cystine supplier and beyond. Amino Acids. 2012;42(1):231–46. https://doi.org/10.1007/s00726-011-0867-5.

    Article  CAS  PubMed  Google Scholar 

  19. Hyde R, Taylor PM, Hundal HS. Amino acid transporters: roles in amino acid sensing and signalling in animal cells. Biochem J. 2003;373(1):1–18. https://doi.org/10.1042/bj20030405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen Y, Swanson RA. Astrocytes and brain injury. J Cereb Blood Flow Metab. 2003;23(2):137–49. https://doi.org/10.1097/01.WCB.0000044631.80210.3C.

    Article  PubMed  Google Scholar 

  21. Jiang Y, Cao Y, Wang Y, Li W, Liu X, Lv Y, Li X, Mi J. Cysteine transporter SLC3A1 promotes breast cancer tumorigenesis. Theranostics. 2017;7(4):1036–46. https://doi.org/10.7150/thno.18005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bannai S, Kitamura E. Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture. J Biol Chem. 1980;255(6):2372–6.

    Article  CAS  PubMed  Google Scholar 

  23. Sato H, Tamba M, Ishii T, Bannai S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem. 1999;274(17):11455–8. https://doi.org/10.1074/jbc.274.17.11455.

    Article  CAS  PubMed  Google Scholar 

  24. Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, Massie A, Smolders I, Methner A, Pergande M, Smith SB, Ganapathy V, Maher P. The cystine/glutamate antiporter system xc− in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxidants Redox Signal. 2013;18(5):522–55. https://doi.org/10.1089/ars.2011.4391.

    Article  CAS  Google Scholar 

  25. Lo M, Wang Y-Z, Gout PW. The xc− cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol. 2008;215(3):593–602. https://doi.org/10.1002/jcp.21366.

    Article  CAS  PubMed  Google Scholar 

  26. Stipanuk MH. Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr. 2004;24(1):539–77. https://doi.org/10.1146/annurev.nutr.24.012003.132418.

    Article  CAS  PubMed  Google Scholar 

  27. Mosharov E, Cranford MR, Banerjee R. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes†. Biochemistry. 2000;39(42):13005–11. https://doi.org/10.1021/bi001088w.

    Article  CAS  PubMed  Google Scholar 

  28. Kimura H. Production and physiological effects of hydrogen sulfide. Antioxid Redox Signal. 2014;20(5):783–93. https://doi.org/10.1089/ars.2013.5309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Szabo C, Papapetropoulos A, Ohlstein EH. International union of basic and clinical pharmacology. CII: pharmacological modulation of H2S levels: H2S donors and H2S biosynthesis inhibitors. Pharmacol Rev. 2017;69(4):497–564. https://doi.org/10.1124/pr.117.014050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Meier M. Structure of human cystathionine beta-synthase: a unique pyridoxal 5′-phosphate-dependent heme protein. EMBO J. 2001;20(15):3910–6. https://doi.org/10.1093/emboj/20.15.3910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zou C-G, Banerjee R. Tumor necrosis factor-α-induced targeted proteolysis of cystathionine β-synthase modulates redox homeostasis. J Biol Chem. 2003;278(19):16802–8. https://doi.org/10.1074/jbc.M212376200.

    Article  CAS  PubMed  Google Scholar 

  32. Ishii I, Akahoshi N, Yamada H, Nakano S, Izumi T, Suematsu M. Cystathionine gamma-Lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury. J Biol Chem. 2010;285(34):26358–68. https://doi.org/10.1074/jbc.M110.147439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Watanabe M, Osada J, Aratani Y, Kluckman K, Reddick R, Malinow MR, Maeda N. Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci U S A. 1995;92(5):1585–9. https://doi.org/10.1073/pnas.92.5.1585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pascal TA, Gaull GE, Beratis NG, Gillam BM, Tallan HH. Cystathionase deficiency: evidence for genetic heterogeneity in primary cystathioninuria. Pediatr Res. 1978;12(2):125–33. https://doi.org/10.1203/00006450-197802000-00012.

    Article  CAS  PubMed  Google Scholar 

  35. Viña J, Vento M, García-Sala F, Puertes IR, Gascó E, Sastre J, Asensi M, Pallardó FV. L-cysteine and glutathione metabolism are impaired in premature infants due to cystathionase deficiency. Am J Clin Nutr. 1995;61(5):1067–9. https://doi.org/10.1093/ajcn/61.4.1067.

    Article  PubMed  Google Scholar 

  36. Zlotkin SH, Anderson GH. The development of cystathionase activity during the first year of life. Pediatr Res. 1982;16(1):65–8. https://doi.org/10.1203/00006450-198201001-00013.

    Article  CAS  PubMed  Google Scholar 

  37. Ghosh MK, Nguyen V, Muller HK, Walker AM. Maternal milk T cells drive development of transgenerational Th1 immunity in offspring thymus. J Immunol. 2016;197(6):2290. https://doi.org/10.4049/jimmunol.1502483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Levring TB, Hansen AK, Nielsen BL, Kongsbak M, von Essen MR, Woetmann A, Ødum N, Bonefeld CM, Geisler C. Activated human CD4+ T cells express transporters for both cysteine and cystine. Sci Rep. 2012;2(1):266. https://doi.org/10.1038/srep00266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010;70(1):68–77. https://doi.org/10.1158/0008-5472.Can-09-2587.

    Article  CAS  PubMed  Google Scholar 

  40. Dickhout JG, Carlisle RE, Jerome DE, Mohammed-Ali Z, Jiang H, Yang G, Mani S, Garg SK, Banerjee R, Kaufman RJ, Maclean KN, Wang R, Austin RC. Integrated stress response modulates cellular redox state via induction of cystathionine γ-lyase. J Biol Chem. 2012;287(10):7603–14. https://doi.org/10.1074/jbc.M111.304576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sbodio JI, Snyder SH, Paul BD. Transcriptional control of amino acid homeostasis is disrupted in Huntington’s disease. Proc Natl Acad Sci U S A. 2016;113(31):8843–8. https://doi.org/10.1073/pnas.1608264113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sbodio JI, Snyder SH, Paul BD. Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington’s disease. Proc Natl Acad Sci. 2018;115(4):780–5. https://doi.org/10.1073/pnas.1717877115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine -lyase. Science. 2008;322(5901):587–90. https://doi.org/10.1126/science.1162667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Orlowski M, Meister A. The gamma-glutamyl cycle: a possible transport system for amino acids. Proc Natl Acad Sci U S A. 1970;67(3):1248–55. https://doi.org/10.1073/pnas.67.3.1248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Traverso N, Ricciarelli R, Nitti M, Marengo B, Furfaro AL, Pronzato MA, Marinari UM, Domenicotti C. Role of glutathione in cancer progression and chemoresistance. Oxidative Med Cell Longev. 2013;2013:972913. https://doi.org/10.1155/2013/972913.

    Article  CAS  Google Scholar 

  46. Zhang H, Forman HJ. Redox regulation of gamma-glutamyl transpeptidase. Am J Respir Cell Mol Biol. 2009;41(5):509–15. https://doi.org/10.1165/rcmb.2009-0169TR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lieberman MW, Wiseman AL, Shi ZZ, Carter BZ, Barrios R, Ou CN, Chevez-Barrios P, Wang Y, Habib GM, Goodman JC, Huang SL, Lebovitz RM, Matzuk MM. Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice. Proc Natl Acad Sci. 1996;93(15):7923–6. https://doi.org/10.1073/pnas.93.15.7923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang H, Forman HJ, Choi J. Gamma-glutamyl transpeptidase in glutathione biosynthesis. Methods Enzymol. 2005;401:468–83. https://doi.org/10.1016/s0076-6879(05)01028-1.

    Article  CAS  PubMed  Google Scholar 

  49. Bloomfield G, Kay RR. Uses and abuses of macropinocytosis. J Cell Sci. 2016;129(14):2697–705. https://doi.org/10.1242/jcs.176149.

    Article  CAS  PubMed  Google Scholar 

  50. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, Grabocka E, Nofal M, Drebin JA, Thompson CB, Rabinowitz JD, Metallo CM, Vander Heiden MG, Bar-Sagi D. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497(7451):633–7. https://doi.org/10.1038/nature12138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bak DW, Bechtel TJ, Falco JA, Weerapana E. Cysteine reactivity across the subcellular universe. Curr Opin Chem Biol. 2019;48:96–105. https://doi.org/10.1016/j.cbpa.2018.11.002.

    Article  CAS  PubMed  Google Scholar 

  52. Davidson SM, Jonas O, Keibler MA, Hou HW, Luengo A, Mayers JR, Wyckoff J, Del Rosario AM, Whitman M, Chin CR, Condon KJ, Lammers A, Kellersberger KA, Stall BK, Stephanopoulos G, Bar-Sagi D, Han J, Rabinowitz JD, Cima MJ, Langer R, Vander Heiden MG. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat Med. 2017;23(2):235–41. https://doi.org/10.1038/nm.4256.

    Article  CAS  PubMed  Google Scholar 

  53. Visscher M, Arkin MR, Dansen TB. Covalent targeting of acquired cysteines in cancer. Curr Opin Chem Biol. 2016;30:61–7. https://doi.org/10.1016/j.cbpa.2015.11.004.

    Article  CAS  PubMed  Google Scholar 

  54. Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009;390(3):191–214. https://doi.org/10.1515/BC.2009.033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kalinina EV, Chernov NN, Novichkova MD. Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes. Biochemistry (Mosc). 2014;79(13):1562–83. https://doi.org/10.1134/s0006297914130082.

    Article  CAS  Google Scholar 

  56. Simon MC, Bansal A. Glutathione metabolism in cancer progression and treatment resistance. J Cell Biol. 2018;217(7):2291–8. https://doi.org/10.1083/jcb.201804161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lu SC. Glutathione synthesis. Biochim Biophys Acta (BBA) Gen Subjects. 2013;1830(5):3143–53. https://doi.org/10.1016/j.bbagen.2012.09.008.

    Article  CAS  Google Scholar 

  58. Lee Z-W, Low Y-L, Huang S, Wang T, Deng L-W. The cystathionine γ-lyase/hydrogen sulfide system maintains cellular glutathione status. Biochem J. 2014;460(3):425–35. https://doi.org/10.1042/BJ20131434.

    Article  CAS  PubMed  Google Scholar 

  59. Stehling O, Lill R. The role of mitochondria in cellular iron-sulfur protein biogenesis: mechanisms, connected processes, and diseases. Cold Spring Harbor Perspect Biol. 2013;5(8):a011312. https://doi.org/10.1101/cshperspect.a011312.

    Article  CAS  Google Scholar 

  60. Novera W, Lee Z-W, Nin DS, Dai MZ-Y, Binte Idres S, Wu H, Damen MA, Tan TZ, Sim AYL, Long YC, Wu W, Huang RY-J, Deng L-W. Cysteine deprivation targets ovarian clear cell carcinoma via oxidative stress and iron−sulfur cluster biogenesis deficit. Antioxid Redox Signal. 2020; https://doi.org/10.1089/ars.2019.7850.

  61. Martinez David L, Tsuchiya Y, Gout I. Coenzyme a biosynthetic machinery in mammalian cells. Biochem Soc Trans. 2014;42(4):1112–7. https://doi.org/10.1042/bst20140124.

    Article  PubMed  Google Scholar 

  62. Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee H-J, Purohit V, Sagalovskiy IR, Ma A, Kapilian J, Firl CEM, Decker AR, Sastra SA, Palermo CF, Andrade LR, Sajjakulnukit P, Zhang L, Tolstyka ZP, Hirschhorn T, Lamb C, Liu T, Gu W, Seeley ES, Stone E, Georgiou G, Manor U, Iuga A, Wahl GM, Stockwell BR, Lyssiotis CA, Olive KP. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science. 2020;368(6486):85–9. https://doi.org/10.1126/science.aaw9872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bebber CM, Müller F, Prieto Clemente L, Weber J, von Karstedt S. Ferroptosis in cancer cell biology. Cancers. 2020;12(1) https://doi.org/10.3390/cancers12010164.

  64. Dixon Scott J, Lemberg Kathryn M, Lamprecht Michael R, Skouta R, Zaitsev Eleina M, Gleason Caroline E, Patel Darpan N, Bauer Andras J, Cantley Alexandra M, Yang Wan S, Morrison B, Stockwell Brent R. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72. https://doi.org/10.1016/j.cell.2012.03.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Li J, Cao F, H-l Y, Z-j H, Lin Z-t, Mao N, Sun B, Wang G. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88. https://doi.org/10.1038/s41419-020-2298-2.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Yang Wan S, SriRamaratnam R, Welsch Matthew E, Shimada K, Skouta R, Viswanathan Vasanthi S, Cheah Jaime H, Clemons Paul A, Shamji Alykhan F, Clish Clary B, Brown Lewis M, Girotti Albert W, Cornish Virginia W, Schreiber Stuart L, Stockwell Brent R. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1-2):317–31. https://doi.org/10.1016/j.cell.2013.12.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Stipanuk MH, Ueki I, Dominy JE, Simmons CR, Hirschberger LL. Cysteine dioxygenase: a robust system for regulation of cellular cysteine levels. Amino Acids. 2008;37(1) https://doi.org/10.1007/s00726-008-0202-y.

  68. Dominy JE, Hwang J, Guo S, Hirschberger LL, Zhang S, Stipanuk MH. Synthesis of amino acid cofactor in cysteine dioxygenase is regulated by substrate and represents a novel post-translational regulation of activity. J Biol Chem. 2008;283(18):12188–201. https://doi.org/10.1074/jbc.M800044200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jurkowska H, Roman HB, Hirschberger LL, Sasakura K, Nagano T, Hanaoka K, Krijt J, Stipanuk MH. Primary hepatocytes from mice lacking cysteine dioxygenase show increased cysteine concentrations and higher rates of metabolism of cysteine to hydrogen sulfide and thiosulfate. Amino Acids. 2014;46(5):1353–65. https://doi.org/10.1007/s00726-014-1700-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rose P, Moore PK, Zhu YZ. H(2)S biosynthesis and catabolism: new insights from molecular studies. Cell Mol Life Sci. 2017;74(8):1391–412. https://doi.org/10.1007/s00018-016-2406-8.

    Article  CAS  PubMed  Google Scholar 

  71. Jeschke J, Hagan HM, Zhang W, Vatapalli R, Calmon MF, Danilova L, Nelkenbrecher C, Van Neste L, Bijsmans ITGW, Van Engeland M, Gabrielson E, Schuebel KE, Winterpacht A, Baylin SB, Herman JG, Ahuja N. Frequent inactivation of em cysteine dioxygenase type 1/em contributes to survival of breast cancer cells and resistance to anthracyclines. Clin Cancer Res. 2013;19(12):3201. https://doi.org/10.1158/1078-0432.CCR-12-3751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hao S, Yu J, He W, Huang Q, Zhao Y, Liang B, Zhang S, Wen Z, Dong S, Rao J, Liao W, Shi M. Cysteine dioxygenase 1 mediates erastin-induced ferroptosis in human gastric cancer cells. Neoplasia. 2017;19(12):1022–32. https://doi.org/10.1016/j.neo.2017.10.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kang YP, Torrente L, Falzone A, Elkins CM, Liu M, Asara JM, Dibble CC, DeNicola GM. Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer. elife. 2019;8 https://doi.org/10.7554/eLife.45572.

  74. Huang CW, Moore PK. H2S synthesizing enzymes: biochemistry and molecular aspects. Handb Exp Pharmacol. 2015;230:3–25. https://doi.org/10.1007/978-3-319-18144-8_1.

    Article  CAS  PubMed  Google Scholar 

  75. Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev. 2012;92(2):791–896. https://doi.org/10.1152/physrev.00017.2011.

    Article  CAS  PubMed  Google Scholar 

  76. Hellmich MR, Szabo C. Hydrogen sulfide and cancer. Handb Exp Pharmacol. 2015;230:233–41. https://doi.org/10.1007/978-3-319-18144-8_12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jurkowska H, Placha W, Nagahara N, Wróbel M. The expression and activity of cystathionine-γ-lyase and 3-mercaptopyruvate sulfurtransferase in human neoplastic cell lines. Amino Acids. 2011;41(1):151–8. https://doi.org/10.1007/s00726-010-0606-3.

    Article  CAS  PubMed  Google Scholar 

  78. Sonke E, Verrydt M, Postenka CO, Pardhan S, Willie CJ, Mazzola CR, Hammers MD, Pluth MD, Lobb I, Power NE, Chambers AF, Leong HS, Sener A. Inhibition of endogenous hydrogen sulfide production in clear-cell renal cell carcinoma cell lines and xenografts restricts their growth, survival and angiogenic potential. Nitric Oxide. 2015;49:26–39. https://doi.org/10.1016/j.niox.2015.06.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Szabo C, Coletta C, Chao C, Modis K, Szczesny B, Papapetropoulos A, Hellmich MR. Tumor-derived hydrogen sulfide, produced by cystathionine- -synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci. 2013;110(30):12474–9. https://doi.org/10.1073/pnas.1306241110.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Untereiner AA, Pavlidou A, Druzhyna N, Papapetropoulos A, Hellmich MR, Szabo C. Drug resistance induces the upregulation of H2S-producing enzymes in HCT116 colon cancer cells. Biochem Pharmacol. 2018;149:174–85. https://doi.org/10.1016/j.bcp.2017.10.007.

    Article  CAS  PubMed  Google Scholar 

  81. Wang YH, Huang JT, Chen WL, Wang RH, Kao MC, Pan YR, Chan SH, Tsai KW, Kung HJ, Lin KT, Wang LH. Dysregulation of cystathionine γ-lyase promotes prostate cancer progression and metastasis. EMBO Rep. 2019c;20(10) https://doi.org/10.15252/embr.201845986.

  82. Leikam C, Hufnagel A, Walz S, Kneitz S, Fekete A, Muller MJ, Eilers M, Scharti M, Meierjohann S. Cystathionase mediates senescence evasion in melanocytes and melanoma cells. Oncogene. 2014;33:771.

    Article  CAS  PubMed  Google Scholar 

  83. Lee ZW, Deng LW. Role of H2S donors in cancer biology. Handb Exp Pharmacol. 2015;230:243–65. https://doi.org/10.1007/978-3-319-18144-8_13.

    Article  CAS  PubMed  Google Scholar 

  84. Nin DS, Idres SB, Song ZJ, Moore PK, Deng LW. Biological effects of morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate and other phosphorothioate-based hydrogen sulfide donors. Antioxid Redox Signal. 2020;32(2):145–58. https://doi.org/10.1089/ars.2019.7896.

    Article  CAS  PubMed  Google Scholar 

  85. Kim J, Hong SJ, Park JH, Park SY, Kim SW, Cho EY, Do IG, Joh JW, Kim DS. Expression of cystathionine beta-synthase is downregulated in hepatocellular carcinoma and associated with poor prognosis. Oncol Rep. 2009;21(6):1449–54. https://doi.org/10.3892/or_00000373.

    Article  CAS  PubMed  Google Scholar 

  86. Zhao H, Li Q, Wang J, Su X, Ng KM, Qiu T, Shan L, Ling Y, Wang L, Cai J, Ying J. Frequent epigenetic silencing of the folate-metabolising gene cystathionine-beta-synthase in gastrointestinal cancer. PLoS One. 2012;7(11):e49683. https://doi.org/10.1371/journal.pone.0049683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pras E, Raben N, Golomb E, Arber N, Aksentijevich I, Schapiro JM, Harel D, Katz G, Liberman U, Pras M, et al. Mutations in the SLC3A1 transporter gene in cystinuria. Am J Hum Genet. 1995;56(6):1297–303.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Sato H, Shiiya A, Kimata M, Maebara K, Tamba M, Sakakura Y, Makino N, Sugiyama F, Yagami K, Moriguchi T, Takahashi S, Bannai S. Redox imbalance in cystine/glutamate transporter-deficient mice. J Biol Chem. 2005;280(45):37423–9. https://doi.org/10.1074/jbc.M506439200.

    Article  CAS  PubMed  Google Scholar 

  89. Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GY, Sontheimer H. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neurosci. 2005;25(31):7101–10. https://doi.org/10.1523/JNEUROSCI.5258-04.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Guo W, Zhao Y, Zhang Z, Tan N, Zhao F, Ge C, Liang L, Jia D, Chen T, Yao M, Li J, He X. Disruption of xCT inhibits cell growth via the ROS/autophagy pathway in hepatocellular carcinoma. Cancer Lett. 2011;312(1):55–61. https://doi.org/10.1016/j.canlet.2011.07.024.

    Article  CAS  PubMed  Google Scholar 

  91. Huang Y, Dai Z, Barbacioru C, Sadée W. Cystine-glutamate transporter SLC7A11 in cancer chemosensitivity and chemoresistance. Cancer Res. 2005;65(16):7446–54. https://doi.org/10.1158/0008-5472.Can-04-4267.

    Article  CAS  PubMed  Google Scholar 

  92. Ji X, Qian J, Rahman SMJ, Siska PJ, Zou Y, Harris BK, Hoeksema MD, Trenary IA, Heidi C, Eisenberg R, Rathmell JC, Young JD, Massion PP. xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression. Oncogene. 2018;37(36):5007–19. https://doi.org/10.1038/s41388-018-0307-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Liu XX, Li XJ, Zhang B, Liang YJ, Zhou CX, Cao DX, He M, Chen GQ, He JR, Zhao Q. MicroRNA-26b is underexpressed in human breast cancer and induces cell apoptosis by targeting SLC7A11. FEBS Lett. 2011;585(9):1363–7. https://doi.org/10.1016/j.febslet.2011.04.018.

    Article  CAS  PubMed  Google Scholar 

  94. Takeuchi S, Wada K, Toyooka T, Shinomiya N, Shimazaki H, Nakanishi K, Nagatani K, Otani N, Osada H, Uozumi Y, Matsuo H, Nawashiro H. Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas. Neurosurgery. 2013;72(1):33–41; discussion 41. https://doi.org/10.1227/NEU.0b013e318276b2de.

    Article  PubMed  Google Scholar 

  95. Timmerman Luika A, Holton T, Yuneva M, Louie Raymond J, Padró M, Daemen A, Hu M, Chan Denise A, Ethier Stephen P, van ‘t Veer Laura J, Polyak K, McCormick F, Gray Joe W. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell. 2013;24(4):450–65. https://doi.org/10.1016/j.ccr.2013.08.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Menegon S, Columbano A, Giordano S. The dual roles of NRF2 in cancer. Trends Mol Med. 2016;22(7):578–93. https://doi.org/10.1016/j.molmed.2016.05.002.

    Article  CAS  PubMed  Google Scholar 

  97. Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell. 2018;34(1):21–43. https://doi.org/10.1016/j.ccell.2018.03.022.

    Article  CAS  PubMed  Google Scholar 

  98. Tonelli C, Chio IIC, Tuveson DA. Transcriptional regulation by Nrf2. Antioxid Redox Signal. 2018;29(17):1727–45. https://doi.org/10.1089/ars.2017.7342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Habib E, Linher-Melville K, Lin H-X, Singh G. Expression of xCT and activity of system xc− are regulated by NRF2 in human breast cancer cells in response to oxidative stress. Redox Biol. 2015;5:33–42. https://doi.org/10.1016/j.redox.2015.03.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ogiwara H, Takahashi K, Sasaki M, Kuroda T, Yoshida H, Watanabe R, Maruyama A, Makinoshima H, Chiwaki F, Sasaki H, Kato T, Okamoto A, Kohno T. Targeting the vulnerability of glutathione metabolism in ARID1A-deficient cancers. Cancer Cell. 2019;35(2):177–190.e178. https://doi.org/10.1016/j.ccell.2018.12.009.

    Article  CAS  PubMed  Google Scholar 

  101. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17(10):1374–95. https://doi.org/10.15252/embr.201642195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Bannai S, Kitamura E. Adaptive enhancement of cystine and glutamate uptake in human diploid fibroblasts in culture. Biochim Biophys Acta (BBA) Mol Cell Res. 1982;721(1):1–10. https://doi.org/10.1016/0167-4889(82)90017-9.

    Article  CAS  Google Scholar 

  103. Sato H, Nomura S, Maebara K, Sato K, Tamba M, Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Biochem Biophys Res Commun. 2004;325(1):109–16. https://doi.org/10.1016/j.bbrc.2004.10.009.

    Article  CAS  PubMed  Google Scholar 

  104. Ye P, Mimura J, Okada T, Sato H, Liu T, Maruyama A, Ohyama C, Itoh K. Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. Mol Cell Biol. 2014;34(18):3421–34. https://doi.org/10.1128/mcb.00221-14.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Martin L, Gardner LB. Stress-induced inhibition of nonsense-mediated RNA decay regulates intracellular cystine transport and intracellular glutathione through regulation of the cystine/glutamate exchanger SLC7A11. Oncogene. 2015;34(32):4211–8. https://doi.org/10.1038/onc.2014.352.

    Article  CAS  PubMed  Google Scholar 

  106. Jiang L, Kon N, Li T, Wang S-J, Su T, Hibshoosh H, Baer R, Gu W. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520(7545):57–62. https://doi.org/10.1038/nature14344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Liu DS, Duong CP, Haupt S, Montgomery KG, House CM, Azar WJ, Pearson HB, Fisher OM, Read M, Guerra GR, Haupt Y, Cullinane C, Wiman KG, Abrahmsen L, Phillips WA, Clemons NJ. Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat Commun. 2017;8(1) https://doi.org/10.1038/ncomms14844.

  108. Linher-Melville K, Haftchenary S, Gunning P, Singh G. Signal transducer and activator of transcription 3 and 5 regulate system xc- and redox balance in human breast cancer cells. Mol Cell Biochem. 2015;405(1-2):205–21. https://doi.org/10.1007/s11010-015-2412-4.

    Article  CAS  PubMed  Google Scholar 

  109. Gu Y, Albuquerque CP, Braas D, Zhang W, Villa GR, Bi J, Ikegami S, Masui K, Gini B, Yang H, Gahman TC, Shiau AK, Cloughesy TF, Christofk HR, Zhou H, Guan K-L, Mischel PS. mTORC2 regulates amino acid metabolism in cancer by phosphorylation of the cystine-glutamate antiporter xCT. Mol Cell. 2017;67(1):128–138.e127. https://doi.org/10.1016/j.molcel.2017.05.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lien EC, Ghisolfi L, Geck RC, Asara JM, Toker A. Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT. Sci Signal. 2017;10(510) https://doi.org/10.1126/scisignal.aao6604.

  111. Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H, Saya H. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc− and thereby promotes tumor growth. Cancer Cell. 2011;19(3):387–400. https://doi.org/10.1016/j.ccr.2011.01.038.

    Article  CAS  PubMed  Google Scholar 

  112. Nagano O, Okazaki S, Saya H. Redox regulation in stem-like cancer cells by CD44 variant isoforms. Oncogene. 2013;32(44):5191–8. https://doi.org/10.1038/onc.2012.638.

    Article  CAS  PubMed  Google Scholar 

  113. Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T, Mogushi K, Tanaka H, Osawa T, Kanki Y, Minami T, Aburatani H, Ohmura M, Kubo A, Suematsu M, Takahashi K, Saya H, Nagano O. Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat Commun. 2012;3(1) https://doi.org/10.1038/ncomms1892.

  114. Hasegawa M, Takahashi H, Rajabi H, Alam M, Suzuki Y, Yin L, Tagde A, Maeda T, Hiraki M, Sukhatme VP, Kufe D. Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells. Oncotarget. 2016;7(11):11756–69. https://doi.org/10.18632/oncotarget.7598.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Tsuchihashi K, Okazaki S, Ohmura M, Ishikawa M, Sampetrean O, Onishi N, Wakimoto H, Yoshikawa M, Seishima R, Iwasaki Y, Morikawa T, Abe S, Takao A, Shimizu M, Masuko T, Nagane M, Furnari FB, Akiyama T, Suematsu M, Baba E, Akashi K, Saya H, Nagano O. The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(−-). Cancer Res. 2016;76(10):2954–63. https://doi.org/10.1158/0008-5472.Can-15-2121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Song X, Zhu S, Chen P, Hou W, Wen Q, Liu J, Xie Y, Liu J, Klionsky DJ, Kroemer G, Lotze MT, Zeh HJ, Kang R, Tang D. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system xc– activity. Curr Biol. 2018;28(15):2388–2399.e2385. https://doi.org/10.1016/j.cub.2018.05.094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Briggs Kimberly J, Koivunen P, Cao S, Backus Keriann M, Olenchock Benjamin A, Patel H, Zhang Q, Signoretti S, Gerfen Gary J, Richardson Andrea L, Witkiewicz Agnieszka K, Cravatt Benjamin F, Clardy J, Kaelin William G. Paracrine induction of HIF by glutamate in breast cancer: EglN1 senses cysteine. Cell. 2016;166(1):126–39. https://doi.org/10.1016/j.cell.2016.05.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Yang Y, Yee D. IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC−. Cancer Res. 2014;74(8):2295–305. https://doi.org/10.1158/0008-5472.Can-13-1803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Harris Isaac S, Treloar Aislinn E, Inoue S, Sasaki M, Gorrini C, Lee Kim C, Yung Ka Y, Brenner D, Knobbe-Thomsen Christiane B, Cox Maureen A, Elia A, Berger T, Cescon David W, Adeoye A, Brüstle A, Molyneux Sam D, Mason Jacqueline M, Li Wanda Y, Yamamoto K, Wakeham A, Berman Hal K, Khokha R, Done Susan J, Kavanagh Terrance J, Lam C-W, Mak Tak W. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell. 2015;27(2):211–22. https://doi.org/10.1016/j.ccell.2014.11.019.

    Article  CAS  PubMed  Google Scholar 

  120. Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Investig. 2013;123(9):3678–84. https://doi.org/10.1172/jci69600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sayin VI, LeBoeuf SE, Singh SX, Davidson SM, Biancur D, Guzelhan BS, Alvarez SW, Wu WL, Karakousi TR, Zavitsanou AM, Ubriaco J, Muir A, Karagiannis D, Morris PJ, Thomas CJ, Possemato R, Vander Heiden MG, Papagiannakopoulos T. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. elife. 2017;6 https://doi.org/10.7554/eLife.28083.

  122. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7(1):11–20. https://doi.org/10.1016/j.cmet.2007.10.002.

    Article  CAS  PubMed  Google Scholar 

  123. Yamaguchi I, Yoshimura SH, Katoh H. High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11). J Biol Chem. 2020;295(20):6936–45. https://doi.org/10.1074/jbc.RA119.012213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Goji T, Takahara K, Negishi M, Katoh H. Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation. J Biol Chem. 2017;292(48):19721–32. https://doi.org/10.1074/jbc.M117.814392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yu L, Teoh ST, Ensink E, Ogrodzinski MP, Yang C, Vazquez AI, Lunt SY. Cysteine catabolism and the serine biosynthesis pathway support pyruvate production during pyruvate kinase knockdown in pancreatic cancer cells. Cancer Metabol. 2019a;7(1) https://doi.org/10.1186/s40170-019-0205-z.

  126. Hanigan MH, Gallagher BC, Townsend DM, Gabarra V. Gamma-glutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo. Carcinogenesis. 1999;20(4):553–9. https://doi.org/10.1093/carcin/20.4.553.

    Article  CAS  PubMed  Google Scholar 

  127. Slaga TJ, Budunova IV, Gimenez-Conti IB, Aldaz CM. The mouse skin carcinogenesis model. J Investig Dermatol Symp Proc. 1996;1(2):151–6.

    CAS  PubMed  Google Scholar 

  128. Hanigan MH. Gamma-glutamyl transpeptidase: redox regulation and drug resistance. Adv Cancer Res. 2014;122:103–41. https://doi.org/10.1016/b978-0-12-420117-0.00003-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Blanco RA, Ziegler TR, Carlson BA, Cheng PY, Park Y, Cotsonis GA, Accardi CJ, Jones DP. Diurnal variation in glutathione and cysteine redox states in human plasma. Am J Clin Nutr. 2007;86(4):1016–23. https://doi.org/10.1093/ajcn/86.4.1016.

    Article  CAS  PubMed  Google Scholar 

  130. Gerber MA, Thung SN. Enzyme patterns in human hepatocellular carcinoma. Am J Pathol. 1980;98(2):395–400.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Luo M, Sun W, Wu C, Zhang L, Liu D, Li W, Mei Q, Hu G. High pretreatment serum gamma-glutamyl transpeptidase predicts an inferior outcome in nasopharyngeal carcinoma. Oncotarget. 2017;8(40):67651–62. https://doi.org/10.18632/oncotarget.18798.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Ahmad S, Okine L, Wood R, Aljian J, Vistica DT. Gamma-Glutamyl transpeptidase (gamma-GT) and maintenance of thiol pools in tumor cells resistant to alkylating agents. J Cell Physiol. 1987;131(2):240–6. https://doi.org/10.1002/jcp.1041310214.

    Article  CAS  PubMed  Google Scholar 

  133. Godwin AK, Meister A, O'Dwyer PJ, Huang CS, Hamilton TC, Anderson ME. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci. 1992;89(7):3070–4. https://doi.org/10.1073/pnas.89.7.3070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Oguchi H, Kikkawa F, Kojima M, Maeda O, Mizuno K, Suganuma N, Kawai M, Tomoda Y. Glutathione related enzymes in cis-diamminedichloroplatinum (II)-sensitive and-resistant human ovarian carcinoma cells. Anticancer Res. 1994;14(1a):193–200.

    CAS  PubMed  Google Scholar 

  135. Lettieri-Barbato D, Aquilano K. Pushing the limits of cancer therapy: the nutrient game. Front Oncol. 2018;8 https://doi.org/10.3389/fonc.2018.00148.

  136. Stepka P, Vsiansky V, Raudenska M, Gumulec J, Adam V, Masarik M. Metabolic and amino acid alterations of the tumor microenvironment. Curr Med Chem. 2020; https://doi.org/10.2174/0929867327666200207114658.

  137. Zhang W, Trachootham D, Liu J, Chen G, Pelicano H, Garcia-Prieto C, Lu W, Burger JA, Croce CM, Plunkett W, Keating MJ, Huang P. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat Cell Biol. 2012;14(3):276–86. https://doi.org/10.1038/ncb2432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wang W, Kryczek I, Dostál L, Lin H, Tan L, Zhao L, Lu F, Wei S, Maj T, Peng D, He G, Vatan L, Szeliga W, Kuick R, Kotarski J, Tarkowski R, Dou Y, Rattan R, Munkarah A, Liu JR, Zou W. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell. 2016;165(5):1092–105. https://doi.org/10.1016/j.cell.2016.04.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Doxsee DW, Gout PW, Kurita T, Lo M, Buckley AR, Wang Y, Xue H, Karp CM, Cutz J-C, Cunha GR, Wang Y-Z. Sulfasalazine-induced cystine starvation: potential use for prostate cancer therapy. Prostate. 2007;67(2):162–71. https://doi.org/10.1002/pros.20508.

    Article  CAS  PubMed  Google Scholar 

  140. Gout PW, Buckley AR, Simms CR, Bruchovsky N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc − cystine transporter: a new action for an old drug. Leukemia. 2001;15(10):1633–40. https://doi.org/10.1038/sj.leu.2402238.

    Article  CAS  PubMed  Google Scholar 

  141. Guan J, Lo M, Dockery P, Mahon S, Karp CM, Buckley AR, Lam S, Gout PW, Wang YZ. The xc- cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine. Cancer Chemother Pharmacol. 2009;64(3):463–72. https://doi.org/10.1007/s00280-008-0894-4.

    Article  CAS  PubMed  Google Scholar 

  142. Patel SA, Warren BA, Rhoderick JF, Bridges RJ. Differentiation of substrate and non-substrate inhibitors of transport system xc(−): an obligate exchanger of L-glutamate and L-cystine. Neuropharmacology. 2004;46(2):273–84. https://doi.org/10.1016/j.neuropharm.2003.08.006.

    Article  CAS  PubMed  Google Scholar 

  143. Massie A, Boillée S, Hewett S, Knackstedt L, Lewerenz J. Main path and byways: non-vesicular glutamate release by system xc−as an important modifier of glutamatergic neurotransmission. J Neurochem. 2015;135(6):1062–79. https://doi.org/10.1111/jnc.13348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lutgen V, Resch J, Qualmann K, Raddatz NJ, Panhans C, Olander EM, Kong L, Choi S, Mantsch JR, Baker DA. Behavioral assessment of acute inhibition of system xc (−) in rats. Psychopharmacology. 2014;231(24):4637–47. https://doi.org/10.1007/s00213-014-3612-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chidley C, Haruki H, Pedersen MG, Muller E, Johnsson K. A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis. Nat Chem Biol. 2011;7(6):375–83. https://doi.org/10.1038/nchembio.557.

    Article  CAS  PubMed  Google Scholar 

  146. Jansen G, van der Heijden J, Oerlemans R, Lems WF, Ifergan I, Scheper RJ, Assaraf YG, Dijkmans BAC. Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications for combination therapies with methotrexate in rheumatoid arthritis. Arthritis Rheum. 2004;50(7):2130–9. https://doi.org/10.1002/art.20375.

    Article  CAS  PubMed  Google Scholar 

  147. Pruzanski W, Stefanski E, Vadas P, Ramamurthy NS. Inhibition of extracellular release of proinflammatory secretory phospholipase A2 (sPLA2) by sulfasalazine: a novel mechanism of anti-inflammatory activity. Biochem Pharmacol. 1997;53(12):1901–7. https://doi.org/10.1016/s0006-2952(97)00137-8.

    Article  CAS  PubMed  Google Scholar 

  148. Wahl C, Liptay S, Adler G, Schmid RM. Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Investig. 1998;101(5):1163–74. https://doi.org/10.1172/jci992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol. 2014;10(1):9–17. https://doi.org/10.1038/nchembio.1416.

    Article  CAS  PubMed  Google Scholar 

  150. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, Kaffenberger SD, Eaton JK, Shimada K, Aguirre AJ, Viswanathan SR, Chattopadhyay S, Tamayo P, Yang WS, Rees MG, Chen S, Boskovic ZV, Javaid S, Huang C, Wu X, Tseng YY, Roider EM, Gao D, Cleary JM, Wolpin BM, Mesirov JP, Haber DA, Engelman JA, Boehm JS, Kotz JD, Hon CS, Chen Y, Hahn WC, Levesque MP, Doench JG, Berens ME, Shamji AF, Clemons PA, Stockwell BR, Schreiber SL. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547(7664):453–7. https://doi.org/10.1038/nature23007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, Thomas AG, Gleason CE, Tatonetti NP, Slusher BS, Stockwell BR. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. elife. 2014;3:e02523. https://doi.org/10.7554/eLife.02523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Sato M, Kusumi R, Hamashima S, Kobayashi S, Sasaki S, Komiyama Y, Izumikawa T, Conrad M, Bannai S, Sato H. The ferroptosis inducer erastin irreversibly inhibits system xc− and synergizes with cisplatin to increase cisplatin’s cytotoxicity in cancer cells. Sci Rep. 2018;8(1) https://doi.org/10.1038/s41598-018-19213-4.

  153. Zhang Y, Tan H, Daniels JD, Zandkarimi F, Liu H, Brown LM, Uchida K, O'Connor OA, Stockwell BR. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem Biol. 2019;26(5):623–633.e629. https://doi.org/10.1016/j.chembiol.2019.01.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Yu M, Gai C, Li Z, Ding D, Zheng J, Zhang W, Lv S, Li W. Targeted exosome-encapsulated erastin induced ferroptosis in triple negative breast cancer cells. Cancer Sci. 2019b;110(10):3173–82. https://doi.org/10.1111/cas.14181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Poursaitidis I, Wang X, Crighton T, Labuschagne C, Mason D, Cramer SL, Triplett K, Roy R, Pardo OE, Seckl MJ, Rowlinson SW, Stone E, Lamb RF. Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine. Cell Rep. 2017;18(11):2547–56. https://doi.org/10.1016/j.celrep.2017.02.054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59(2):298–308. https://doi.org/10.1016/j.molcel.2015.06.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, Jiang X. Role of mitochondria in ferroptosis. Mol Cell. 2019;73(2):354–363.e353. https://doi.org/10.1016/j.molcel.2018.10.042.

    Article  CAS  PubMed  Google Scholar 

  158. Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, Sabatini DM, Birsoy K, Possemato R. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017;551(7682):639–43. https://doi.org/10.1038/nature24637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Lang X, Green MD, Wang W, Yu J, Choi JE, Jiang L, Liao P, Zhou J, Zhang Q, Dow A, Saripalli AL, Kryczek I, Wei S, Szeliga W, Vatan L, Stone EM, Georgiou G, Cieslik M, Wahl DR, Morgan MA, Chinnaiyan AM, Lawrence TS, Zou W. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 2019;9(12):1673–85. https://doi.org/10.1158/2159-8290.Cd-19-0338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, Liao P, Lang X, Kryczek I, Sell A, Xia H, Zhou J, Li G, Li J, Li W, Wei S, Vatan L, Zhang H, Szeliga W, Gu W, Liu R, Lawrence TS, Lamb C, Tanno Y, Cieslik M, Stone E, Georgiou G, Chan TA, Chinnaiyan A, Zou W. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019b;569(7755):270–4. https://doi.org/10.1038/s41586-019-1170-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Keating MJ, Holmes R, Lerner S, Ho DH. L-asparaginase and PEG asparaginase--past, present, and future. Leuk Lymphoma. 1993;10(Suppl):153–7. https://doi.org/10.3109/10428199309149129.

    Article  PubMed  Google Scholar 

  162. Jones CL, Stevens BM, D’Alessandro A, Culp-Hill R, Reisz JA, Pei S, Gustafson A, Khan N, DeGregori J, Pollyea DA, Jordan CT. Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II. Blood. 2019;134(4):389–94. https://doi.org/10.1182/blood.2019898114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Uren JR, Lazarus H. L-cyst(e)ine requirements of malignant cells and progress toward depletion therapy. Cancer Treat Rep. 1979;63(6):1073–9.

    CAS  PubMed  Google Scholar 

  164. Cramer SL, Saha A, Liu J, Tadi S, Tiziani S, Yan W, Triplett K, Lamb C, Alters SE, Rowlinson S, Zhang YJ, Keating MJ, Huang P, DiGiovanni J, Georgiou G, Stone E. Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat Med. 2016;23(1):120–7. https://doi.org/10.1038/nm.4232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Bhattacharyya S, Saha S, Giri K, Lanza IR, Nair KS, Jennings NB, Rodriguez-Aguayo C, Lopez-Berestein G, Basal E, Weaver AL, Visscher DW, Cliby W, Sood AK, Bhattacharya R, Mukherjee P. Cystathionine Beta-synthase (CBS) contributes to advanced ovarian Cancer progression and drug resistance. PLoS One. 2013;8:e79167.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Cochrane DR, Tessier-Cloutier B, Lawrence KM, Nazeran T, Karnezis AN, Salamanca C, Cheng AS, McAlpine JN, Hoang LN, Gilks CB, Huntsman DG. Clear cell and endometrioid carcinomas: are their differences attributable to distinct cells of origin? J Pathol. 2017;243(1):26–36. https://doi.org/10.1002/path.4934.

    Article  CAS  PubMed  Google Scholar 

  167. Poisson LM, Munkarah A, Madi H, Datta I, Hensley-Alford S, Tebbe C, Buekers T, Giri S, Rattan R. A metabolomic approach to identifying platinum resistance in ovarian cancer. J Ovarian Res. 2015;8(1):13. https://doi.org/10.1186/s13048-015-0140-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Asimakopoulou A, Panopoulos P, Chasapis CT, Coletta C, Zhou Z, Cirino G, Giannis A, Szabo C, Spyroulias GA, Papapetropoulos A. Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). Br J Pharmacol. 2013;169(4):922–32. https://doi.org/10.1111/bph.12171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Yue T, Zuo S, Bu D, Zhu J, Chen S, Ma Y, Ma J, Guo S, Wen L, Zhang X, Hu J, Wang Y, Yao Z, Chen G, Wang X, Pan Y, Wang P, Liu Y. Aminooxyacetic acid (AOAA) sensitizes colon cancer cells to oxaliplatin via exaggerating apoptosis induced by ROS. J Cancer. 2020;11(7):1828–38. https://doi.org/10.7150/jca.35375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Wang L, Cai H, Hu Y, Liu F, Huang S, Zhou Y, Yu J, Xu J, Wu F. A pharmacological probe identifies cystathionine β-synthase as a new negative regulator for ferroptosis. Cell Death Dis. 2018;9(10):1005. https://doi.org/10.1038/s41419-018-1063-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Wang L, Shi H, Zhang X, Zhang X, Liu Y, Kang W, Shi X, Wang T. I157172, a novel inhibitor of cystathionine γ-lyase, inhibits growth and migration of breast cancer cells via SIRT1-mediated deacetylation of STAT3. Oncol Rep. 2019a;41(1):427–36. https://doi.org/10.3892/or.2018.6798.

    Article  CAS  PubMed  Google Scholar 

  172. Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan C-H, van den Berg S, Deng L-W, Moore PK, Karlberg T, Sivaraman J. Structural basis for the inhibition mechanism of human cystathionine γ-lyase, an enzyme responsible for the production of H2S. J Biol Chem. 2009;284(5):3076–85. https://doi.org/10.1074/jbc.M805459200.

    Article  CAS  PubMed  Google Scholar 

  173. Clausen T, Huber R, Prade L, Wahl MC, Messerschmidt A. Crystal structure of Escherichia coli cystathionine γ-synthase at 1.5 Å resolution. EMBO J. 1998;17(23):6827–38. https://doi.org/10.1093/emboj/17.23.6827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP–dependent transporters. Nat Rev Cancer. 2002;2(1):48–58. https://doi.org/10.1038/nrc706.

    Article  CAS  PubMed  Google Scholar 

  175. Manciu L, Chang X-B, Buyse F, Hou Y-X, Gustot A, Riordan JR, Ruysschaert JM. Intermediate structural states involved in MRP1-mediated drug transport. J Biol Chem. 2003;278(5):3347–56. https://doi.org/10.1074/jbc.M207963200.

    Article  CAS  PubMed  Google Scholar 

  176. Jensen GL, Meister A. Radioprotection of human lymphoid cells by exogenously supplied glutathione is mediated by gamma-glutamyl transpeptidase. Proc Natl Acad Sci. 1983;80(15):4714–7. https://doi.org/10.1073/pnas.80.15.4714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Green JA, Vistica DT, Young RC, Hamilton TC, Rogan AM, Ozols RF. Potentiation of melphalan cytotoxicity in human ovarian cancer cell lines by glutathione depletion. Cancer Res. 1984;44(11):5427–31.

    CAS  PubMed  Google Scholar 

  178. Ozols RF, Louie KG, Plowman J, Behrens BC, Fine RL, Dykes D, Hamilton TC. Enhanced melphalan cytotoxicity in human ovarian cancer in vitro and in tumor-bearing nude mice by buthionine sulfoximine depletion of glutathione. Biochem Pharmacol. 1987;36(1):147–53. https://doi.org/10.1016/0006-2952(87)90392-3.

    Article  CAS  PubMed  Google Scholar 

  179. Russo A, DeGraff W, Friedman N, Mitchell JB. Selective modulation of glutathione levels in human normal versus tumor cells and subsequent differential response to chemotherapy drugs. Cancer Res. 1986;46(6):2845–8.

    CAS  PubMed  Google Scholar 

  180. Dai Z, Huang Y, Sadee W, Blower P. Chemoinformatics analysis identifies cytotoxic compounds susceptible to chemoresistance mediated by glutathione and cystine/glutamate transport system xc. J Med Chem. 2007;50(8):1896–906. https://doi.org/10.1021/jm060960h.

    Article  CAS  PubMed  Google Scholar 

  181. Okuno S, Sato H, Kuriyama-Matsumura K, Tamba M, Wang H, Sohda S, Hamada H, Yoshikawa H, Kondo T, Bannai S. Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines. Br J Cancer. 2003;88(6):951–6. https://doi.org/10.1038/sj.bjc.6600786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Hansson J, Edgren M, Ehrsson H, Ringborg U, Nilsson B. Effect of D,L-buthionine-S,R-sulfoximine on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic drugs in human melanoma cells. Cancer Res. 1988;48(1):19–26.

    CAS  PubMed  Google Scholar 

  183. Lien EC, Lyssiotis CA, Juvekar A, Hu H, Asara JM, Cantley LC, Toker A. Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer. Nat Cell Biol. 2016;18(5):572–8. https://doi.org/10.1038/ncb3341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Nunes SC, Ramos C, Lopes-Coelho F, Sequeira CO, Silva F, Gouveia-Fernandes S, Rodrigues A, Guimarães A, Silveira M, Abreu S, Santo VE, Brito C, Félix A, Pereira SA, Serpa J. Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity. Sci Rep. 2018;8(1):9513. https://doi.org/10.1038/s41598-018-27753-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Pendyala L, Velagapudi S, Toth K, Zdanowicz J, Glaves D, Slocum H, Perez R, Huben R, Creaven PJ, Raghavan D. Translational studies of glutathione in bladder cancer cell lines and human specimens. Clin Cancer Res. 1997;3(5):793–8.

    CAS  PubMed  Google Scholar 

  186. Révész L, Edgren MR, Wainson AA. Selective toxicity of buthionine sulfoximine (BSO) to melanoma cells in vitro and in vivo. Int J Radiat Oncol Biol Phys. 1994;29(2):403–6. https://doi.org/10.1016/0360-3016(94)90298-4.

    Article  PubMed  Google Scholar 

  187. Rocha CRR, Garcia CCM, Vieira DB, Quinet A, de Andrade-Lima LC, Munford V, Belizário JE, Menck CFM. Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo. Cell Death Dis. 2014;5(10):–e1505. https://doi.org/10.1038/cddis.2014.465.

  188. Zheng Z-G, Xu H, Suo S-S, Xu X-L, Ni M-W, Gu L-H, Chen W, Wang L-Y, Zhao Y, Tian B, Hua Y-J. The essential role of H19 contributing to cisplatin resistance by regulating glutathione metabolism in high-grade serous ovarian cancer. Sci Rep. 2016;6(1):26093. https://doi.org/10.1038/srep26093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Bekeschus S, Eisenmann S, Sagwal SK, Bodnar Y, Moritz J, Poschkamp B, Stoffels I, Emmert S, Madesh M, Weltmann K-D, von Woedtke T, Gandhirajan RK. xCT (SLC7A11) expression confers intrinsic resistance to physical plasma treatment in tumor cells. Redox Biol. 2020;30:101423. https://doi.org/10.1016/j.redox.2019.101423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Nunes S, Serpa J. Glutathione in ovarian cancer: a double-edged sword. Int J Mol Sci. 2018;19(7) https://doi.org/10.3390/ijms19071882.

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  1. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Dawn Sijin Nin, Shabana Binte Idres & Lih-Wen Deng

  2. National University Cancer Institute, National University Health System, Singapore, Singapore

    Lih-Wen Deng

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  1. Basic Medical Science & Forensic Medicine, West China Hospital of Sichuan University, Chengdu, China

    Canhua Huang

  2. Department of Pharmacology, West China Hospital of Sichuan University, Chengdu, China

    Yuanyuan Zhang

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Nin, D.S., Idres, S.B., Deng, LW. (2021). Cysteine Metabolism in Cancer Progression and Therapy Resistance. In: Huang, C., Zhang, Y. (eds) Oxidative Stress. Springer, Singapore. https://doi.org/10.1007/978-981-16-0522-2_7

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