Skip to main content
SpringerLink
Log in

Glutathione Synthesis in Cancer Cells

  • REVIEW
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Tripeptide GSH is associated not only with the control and maintenance of redox cell homeostasis, but also with the processes of detoxification, proliferation, cell differentiation, and regulation of cell death. Disruptions in GSH synthesis and changes in the GSH/GSSG ratio are common for many pathological conditions, including malignant neoplasms. Numerous data indicate the importance of GSH and the GSH/GSSG ratio in the regulation of tumor cell viability, in the initiation of tumor development, progression, and drug resistance. However, control of the mechanism of GSH synthesis in malignant tumors remains poorly understood. This review discusses the features of GSH synthesis and its regulation in tumor cells. The role of GSH in the mechanisms of apoptosis, necroptosis, ferroptosis, and autophagy is considered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

Abbreviations

γ-GCL:

γ-glutamate cysteine ligase

GGT:

γ-glutamyl transferase

BSO:

L-buthionine-(S, R)-sulfoximine

GPx:

glutathione peroxidase

GSH and GSSG:

reduced and oxidized glutathione, respectively

MAPK:

mitogen-activated protein kinase

miR:

microRNA

Nrf2:

NF-E2-related factor 2

ROS:

reactive oxygen species

REFERENCES

  1. Scirè, A., Cianfruglia, L., Minnelli, C., Bartolini, D., Torquato, P., Principato, G., Galli, F., and Armeni, T. (2019) Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways, Biofactors, 45, 152-168, doi: https://doi.org/10.1002/biof.1476.

    Article  CAS  PubMed  Google Scholar 

  2. Kalinina, E. V., Chernov, N. N., and Novichkova, M. D. (2014) Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes, Biochemistry (Moscow), 79, 1562-1583, doi: https://doi.org/10.1134/S0006297914130082.

    Article  CAS  Google Scholar 

  3. Dwivedi, D., Megha, K., Mishra, R., and Mandal, P. K. (2020) Glutathione in brain: overview of its conformations, functions, biochemical characteristics, quantitation and potential therapeutic role in brain disorders, Neurochem. Res., 45, 1461-1480, doi: https://doi.org/10.1007/s11064-020-03030-1.

    Article  CAS  PubMed  Google Scholar 

  4. Teskey, G., Abrahem, R., Cao, R., Gyurjian, K., Islamoglu, H., Lucero, M., Martinez, A., Paredes, E., Salaiz, O., Robinson, B., and Venketaraman, V. (2018) Glutathione as a marker for human disease, Adv. Clin. Chem., 87, 141-159, doi: https://doi.org/10.1016/bs.acc.2018.07.004.

    Article  PubMed  Google Scholar 

  5. Xiao, Y., and Meierhofer, D. (2019) Glutathione metabolism in renal cell carcinoma progression and implications for therapies, Int. J. Mol. Sci., 20, 3672, doi: https://doi.org/10.3390/ijms20153672.

    Article  CAS  PubMed Central  Google Scholar 

  6. Bansal, A., and Simon, M. C. (2018) Glutathione metabolism in cancer progression and treatment resistance, J. Cell Biol., 217, 2291-2298, doi: https://doi.org/10.1083/jcb.201804161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Galadari, S., Rahman, A., Pallichankandy, S., and Thayyullathil, F. (2017) Reactive oxygen species and cancer paradox: to promote or to suppress? Free Radic. Biol. Med., 104, 144-164, doi: https://doi.org/10.1016/j.freeradbiomed.2017.01.004.

    Article  CAS  PubMed  Google Scholar 

  8. Chatterjee, A., and Gupta, S. (2018) The Multifaceted role of glutathione S-transferases in cancer, Cancer Lett., 433, 33-42, doi: https://doi.org/10.1016/j.canlet.2018.06.028.

    Article  CAS  PubMed  Google Scholar 

  9. Desideri, E., Ciccarone, F., and Ciriolo, M. R. (2019) Targeting glutathione metabolism: partner in crime in anticancer therapy, Nutrients, 11, 1926, doi: https://doi.org/10.3390/nu11081926.

    Article  CAS  PubMed Central  Google Scholar 

  10. Kengen, J., Deglasse, J. P., Neveu, M. A., Mignion, L., Desmet, C., Gourgue, F., Jonas, J. C., Gallez, B., and Jordan, B. F. (2018) Biomarkers of tumour redox status in response to modulations of glutathione and thioredoxin antioxidant pathways, Free Radic. Res., 52, 256-266, doi: https://doi.org/10.1080/10715762.2018.1427236.

    Article  CAS  PubMed  Google Scholar 

  11. Kirtonia, A., Sethi, G., and Garg, M. (2020) The multifaceted role of reactive oxygen species in tumorigenesis, Cell. Mol. Life Sci., doi: https://doi.org/10.1007/s00018-020-03536-5.

  12. Xiao, Y., Yang, H., and Lu, J. (2019) Serum gamma-glutamyltransferase and the overall survival of metastatic pancreatic cancer, BMC Cancer, 19, 1020, doi: https://doi.org/10.1186/s12885-019-6250-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huang, Z. Z., Chen, C., Zeng, Z., Yang, H., Oh, J., Chen, L., and Lu, S. C. (2001) Mechanism and significance of increased glutathione level in human hepatocellular carcinoma and liver regeneration, FASEB J., 15, 19-21, doi: https://doi.org/10.1096/fj.00-0445fje.

    Article  PubMed  Google Scholar 

  14. Lu, S. C. (2013) Glutathione synthesis, Biochim. Biophys. Acta, 1830, 3143-3153, doi: https://doi.org/10.1016/j.bbagen.2012.09.008.

    Article  CAS  PubMed  Google Scholar 

  15. Ookhtens, M., and Kaplowitz, N. (1998) Role of the liver in interorgan homeostasis of glutathione and cyst(e)ine, Semin. Liver Dis., 18, 313-329, doi: https://doi.org/10.1055/s-2007-1007167.

    Article  CAS  PubMed  Google Scholar 

  16. Lu, S. C. (2009) Regulation of glutathione synthesis, Mol. Aspects Med., 30, 42-59, doi: https://doi.org/10.1016/j.mam.2008.05.005.

    Article  CAS  PubMed  Google Scholar 

  17. Lien, E. C., Lyssiotis, C. A., Juvekar, A., Hu, H., Asara, J. M., Cantley, L. C., and Toker, A. (2016) Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer, Nat. Cell Biol., 18, 572-578, doi: https://doi.org/10.1038/ncb3341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ristoff, E., and Larsson, A. (2007) Inborn errors in the metabolism of glutathione, Orphanet J. Rare Dis., 2, 16, doi: https://doi.org/10.1186/1750-1172-2-16.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Huseby, N. E., Ravuri, C., and Moens, U. (2016) The proteasome inhibitor lactacystin enhances GSH synthesis capacity by increased expression of antioxidant components in an Nrf2-independent, but p38 MAPK-dependent manner in rat colorectal carcinoma cells, Free Radic. Res., 50, 1-13, doi: https://doi.org/10.3109/10715762.2015.1100730.

    Article  CAS  PubMed  Google Scholar 

  20. Koyani, C. N., Kitz, K., Rossmann, C., Bernhart, E., Huber, E., Trummer, C., Windischhofer, W., Sattler, W., and Malle, E. (2016) Activation of the MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis protects MG-63 osteosarcoma cells against 15d-PGJ2-mediated cell death, Biochem. Pharmacol., 104, 29-41, doi: https://doi.org/10.1016/j.bcp.2016.01.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hiyama, N., Ando, T., Maemura, K., Sakatani, T., Amano, Y., Watanabe, K., Kage, H., Yatomi, Y., Nagase, T., Nakajima, J., and Takai, D. (2018) Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma, Jpn. J. Clin. Oncol., 48, 303-307, doi: https://doi.org/10.1093/jjco/hyy013.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dequanter, D., Van De Velde, M., Bar, I., Nuyens, V., Rousseau, A., Nagy, N., Vanhamme, L., Vanhaeverbeek, M., Brohée, D., Delrée, P., Boudjeltia, K., Lothaire, P., and Uzureau, P. (2016) Nuclear localization of glutamate-cysteine ligase is associated with proliferation in head and neck squamous cell carcinoma, Oncol. Lett., 11, 3660-3668, doi: https://doi.org/10.3892/ol.2016.4458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tatebe, S., Unate, H., Sinicrope, F. A., Sakatani, T., Sugamura, K., Makino, M., Ito, H., Savaraj, N., Kaibara, N., and Kuo, M. T. (2002) Expression of heavy subunit of gamma-glutamylcysteine synthetase (gamma-GCSh) in human colorectal carcinoma, Int. J. Cancer, 97, 21-27, doi: https://doi.org/10.1002/ijc.1574.

    Article  CAS  PubMed  Google Scholar 

  24. Li, M., Zhang, Z., Yuan, J., Zhang, Y., and Jin, X. (2014) Altered glutamate cysteine ligase expression and activity in renal cell carcinoma, Biomed. Rep., 2, 831-834, doi: https://doi.org/10.3892/br.2014.359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Syu, J. P., Chi, J. T., and Kung, H. N. (2016) Nrf2 is the key to chemotherapy resistance in MCF7 breast cancer cells under hypoxia, Oncotarget, 7, 14659-14672, doi: https://doi.org/10.18632/oncotarget.7406.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Njålsson, R., and Norgren, S. (2005) Physiological and pathological aspects of GSH metabolism, Acta Paediatr., 94, 132-137, doi: https://doi.org/10.1111/j.1651-2227.2005.tb01878.x.

    Article  PubMed  Google Scholar 

  27. Njålsson, R., Carlsson, K., Winkler, A., Larsson, A., and Norgren, S. (2003) Diagnostics in patients with glutathione synthetase deficiency but without mutations in the exons of the GSS gene, Hum. Mutat., 22, 14659-14672, doi: https://doi.org/10.1002/humu.9199.

    Article  CAS  Google Scholar 

  28. Li, X., Ding, Y., Liu, Y., Ma, Y., Song, J., Wang, Q., and Yang, Y. (2015) Five Chinese patients with 5-oxoprolinuria due to glutathione synthetase and 5-oxoprolinase deficiencies, Brain Dev., 37, 952-959, doi: https://doi.org/10.1016/j.braindev.2015.03.005.

    Article  PubMed  Google Scholar 

  29. Winkler, A., Njalsson, R., Carlsson, K., Elgadi, A., Rozell, B., Abraham, L., Ersal, N., Shi, Z. Z., Lieberman, M. W., Larsson, A., and Norgren, S. (2011) Glutathione is essential for early embryogenesis-analysis of a glutathione synthetase knockout mouse, Biochem. Biophys. Res. Commun., 412, 121-126, doi: https://doi.org/10.1016/j.bbrc.2011.07.056.

    Article  CAS  PubMed  Google Scholar 

  30. Ke, H. L., Lin, J., Ye, Y., Wu, W. J., Lin, H. H., Wei, H., Huang, M., Chang, D. W., Dinney, C. P., and Wu, X. (2015) Genetic variations in glutathione pathway genes predict cancer recurrence in patients treated with transurethral resection and Bacillus Calmette–Guerin instillation for non-muscle invasive bladder cancer, Ann. Surg. Oncol., 22, 4104-4110, doi: https://doi.org/10.1245/s10434-015-4431-5.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Strohkamp, S., Gemoll, T., Humborg, S., Hartwig, S., Lehr, S., Freitag-Wolf, S., Becker, S., Franzén, B., Pries, R., Wollenberg, B., Roblick, U. J., Bruch, H. P., Keck, T., Auer, G., and Habermann, J. K. (2018) Protein levels of clusterin and glutathione synthetase in platelets allow for early detection of colorectal cancer, Cell. Mol. Life Sci., 75, 323-334, doi: https://doi.org/10.1007/s00018-017-2631-9.

    Article  CAS  PubMed  Google Scholar 

  32. Terzyan, S. S., Burgett, A. W. G., Heroux, A., Smith, C. A., Mooers, B. H., and Hanigan, M. H. (2015) Human γ-glutamyl transpeptidase 1: structures of the free enzyme, inhibitor-bound tetrahedral transition states, and glutamate-bound enzyme reveal novel movement within the active site during catalysis, J. Biol. Chem., 290, 17576-17586, doi: https://doi.org/10.1074/jbc.M115.659680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hofbauer, S. L., Stangl, K. I., de Martino, M., Lucca, I., Haitel, A., Shariat, S. F., and Klatte, T. (2014) Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma, Br. J. Cancer, 111, 1526-1531, doi: https://doi.org/10.1038/bjc.2014.450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Corti, A., Franzini, M., Paolicchi, A., and Pompella, A. (2010) Gamma-glutamyltransferase of cancer cells at the crossroads of tumor progression, drug resistance and drug targeting, Anticancer Res., 30, 1169-1181.

    CAS  PubMed  Google Scholar 

  35. Lu, E., Wolfrey, F. D., Muppidi, J. R., Xu, Y., and Cyster, J. G. (2019) S-geranylgeranyl-L-glutathione is a ligand for human B-cell confinement receptor P2RY, Nature, 567, 244-248, doi: https://doi.org/10.1038/s41586-019-1003-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ramsay, E. E., and Dilda, P. J. (2014) Glutathione S-conjugates as prodrugs to target drug-resistant tumors, Front. Pharmacol., 5, 181, doi: https://doi.org/10.3389/fphar.2014.00181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lu, S. C., and Mato, J. M. (2012) S-adenosylmethionine in liver health, injury, and cancer, Physiol. Rev., 92, 1515-1542, doi: https://doi.org/10.1152/physrev.00047.2011.

    Article  CAS  PubMed  Google Scholar 

  38. Kredich, N. M. (2008) Biosynthesis of cysteine, EcoSal Plus, 3, 1-30, doi: https://doi.org/10.1128/ecosalplus.3.6.1.11.

    Article  CAS  Google Scholar 

  39. Hakimi, A. A., Reznik, E., Lee, C.-H., Creighton, C. J., Brannon, A. R., Luna, A., Aksoy, B. A., Liu, E. M., Shen, R., and Lee, W. (2016) An integrated metabolic atlas of clear cell renal cell carcinoma, Cancer Cell, 29, 104-116, doi: https://doi.org/10.1016/j.ccell.2015.12.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shin, C. S., Mishra, P., Watrous, J. D., Carelli, V., D’Aurelio, M., Jain, M., and Chan, D. C. (2017) The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility, Nat. Commun., 8, 5074, doi: https://doi.org/10.1038/ncomms15074.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Lewerenz, J., Hewett, S. J., Huang, Y., Lambros, M., Gout, P. W., Kalivas, P. W., Massie, A., Smolders, I., Methner, A., Pergande, M., Smith, S. B., Ganapathy, V., and Maher, P. (2013) The cystine/glutamate antiporter system xc– in health and disease: from molecular mechanisms to novel therapeutic opportunities, Antioxid. Redox Signal., 18, 522-555, doi: https://doi.org/10.1089/ars.2011.4391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lim, J. K. M., Delaidelli, A., Minaker, S. W., Zhang, H. F., Colovic, M., Yang, H., Negri, G. L., von Karstedt, S., Lockwood, W. W., Schaffer, P., Leprivier, G., and Sorensen, P. H. (2019) Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic Russian Academy of Sciences transformation by preserving intracellular redox balance, Proc. Natl. Acad. Sci. USA, 116, 9433-9442, doi: https://doi.org/10.1073/pnas.1821323116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang, J., Pavlova, N. N., and Thompson, C. B. (2017) Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine, EMBO J., 36, 1302-1315, doi: https://doi.org/10.15252/embj.201696151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang, L., Venneti, S., and Nagrath, D. (2017) Glutaminolysis: a hallmark of cancer metabolism, Annu. Rev. Biomed. Eng., 19, 163-194, doi: https://doi.org/10.1146/annurev-bioeng-071516-044546.

    Article  CAS  PubMed  Google Scholar 

  46. Gao, P., Tchernyshyov, I., Chang, T. C., Lee, Y. S., Kita, K., Ochi, T., Zeller, K. I., De Marzo, A. M., Van Eyk, J. E., Mendell, J. T., and Dang, C. V. (2009) cMyc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism, Nature, 458, 762-765, doi: https://doi.org/10.1038/nature07823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Altman, B. J., Stine, Z. E., and Dang, C. V. (2016) From Krebs to clinic: Glutamine metabolism to cancer therapy, Nat. Rev. Cancer, 16, 619-634, doi: https://doi.org/10.1038/nrc.2016.71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., Sasaki, A. T., Anastasiou, D., Mullarky, E., Vokes, N. I., Sasaki, M., Beroukhim, R., Stephanopoulos, G., Ligon, A. H., Meyerson, M., Richardson, A. L., Chin, L., Wagner, G., Asara, J. M., Brugge, J. S., Cantley, L. C., and Van der Heiden, M. G. (2011) Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis, Nat. Genet., 43, 869-874, doi: https://doi.org/10.1038/ng.890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A. L., Kafri, R., Kirschner, M. W., Clish, C. B., and Mootha, V. K. (2012) Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation, Science, 336, 1040-1044, doi: https://doi.org/10.1126/science.1218595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang, Z. Z., Lee, E. E., Sudderth, J., Yue, Y., Zia, A., Glass, D., Deberardinis, R. J., and Wang, R. C. (2016) Glutathione depletion, pentose phosphate pathway activation, and hemolysis in erythrocytes protecting cancer cells from vitamin C-induced oxidative stress, J. Biol. Chem., 291, 22861-22867, doi: https://doi.org/10.1074/jbc.C116.748848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li, B., Qiu, B., Lee, D. S. M., Walton, Z. E., Ochocki, J. D., Mathew, L. K., Mancuso, A., Gade, T. P., Keith, B., Nissim, I., and Simon, M. C. (2014) Fructose-1,6-bisphosphatase opposes renal carcinoma progression, Nature, 513, 251-255, doi: https://doi.org/10.1038/nature13557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Anderton, B., Camarda, R., Balakrishnan, S., Balakrishnan, A., Kohnz, R. A., Lim, L., Evason, K. J., Momcilovic, O., Kruttwig, K., Huang, Q., Xu, G., Nomura, D. K., and Goga, A. (2017) MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer, EMBO Rep., 18, 569-585, doi: https://doi.org/10.15252/embr.201643068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hsu, T. I., Hsu, C. H., Lee, K. H., Lin, J. T., Chen, C. S., Chang, K. C., Su, C. Y., Hsiao, M., and Lu, P. J. (2014) MicroRNA-18a is elevated in prostate cancer and promotes tumorigenesis through suppressing STK4 in vitro and in vivo, Oncogenesis, 3, 99, doi: https://doi.org/10.1038/oncsis.2014.12.

    Article  CAS  Google Scholar 

  54. Liu, Z., Wang, J., Li, Y., Fan, J., Chen, L., and Xu, R. (2017) MicroRNA-153 regulates glutamine metabolism in glioblastoma through targeting glutaminase, Tumour Biol., 39, 1010428317691429, doi: https://doi.org/10.1177/1010428317691429.

    Article  CAS  PubMed  Google Scholar 

  55. Espinosa-Diez, C., Fierro-Fernandez, M., Sanchez-Gomez, F., Rodríguez-Pascual, F., Alique, M., Ruiz-Ortega, M., Beraza, N., Martínez-Chantar, M. L., Fernández-Hernando, C., and Lamas, S. (2015) Targeting of gamma-glutamyl-cysteine ligase by miR-433 reduces glutathione biosynthesis and promotes TGF-b-dependent fibrogenesis, Antioxid. Redox Signal., 23, 1092-1105, doi: https://doi.org/10.1089/ars.2014.6025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liang, T., Guo, Q., Li, L., Cheng, Y., Ren, C., and Zhang, G. (2016) MicroRNA-433 inhibits migration and invasion of ovarian cancer cells via targeting Notch1, Neoplasma, 63, 696-704, doi: https://doi.org/10.4149/neo_2016_506.

    Article  CAS  PubMed  Google Scholar 

  57. Li, H., Li, J., Yang, T., Lin, S., and Li, H. (2018) MicroRNA-433 represses proliferation and invasion of colon cancer cells by targeting homeobox A1, Oncol. Res., 26, 315-322, doi: https://doi.org/10.3727/096504017X15067856789781.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Tak, H., Kang, H., Ji, E., Hong, Y., Kim, W., and Lee, E. K. (2018) Potential use of TIA-1, MFF, microRNA-200a-3p, and microRNA-27 as a novel marker for hepatocellular carcinoma, Biochem. Biophys. Res. Commun., 497, 1117-1122, doi: https://doi.org/10.1016/j.bbrc.2018.02.189.

    Article  CAS  PubMed  Google Scholar 

  59. Tili, E., Michaille, J. J., Luo, Z., Volinia, S., Rassenti, L. Z., Kipps, T. J., and Croce, C. M. (2012) The down-regulation of miR-125b in chronic lymphocytic leukemias leads to metabolic adaptation of cells to a transformed state, Blood, 120, 2631-2638, doi: https://doi.org/10.1182/blood-2012-03-415737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, F., Li, L., Chen, Z., Zhu, M., and Gu, Y. (2016) MicroRNA-214 acts as oncogene in breast cancer by targeting the PTENPI3K/Akt signaling pathway, Int. J. Mol. Med., 37, 1421-1428, doi: https://doi.org/10.3892/ijmm.2016.2518.

    Article  CAS  PubMed  Google Scholar 

  61. Zhao, X., Lu, C., Chu, W., Zhang, Y., Zhang, B., Zeng, Q., Wang, R., Li, Z., Lv, B., and Liu, J. (2016) MicroRNA-214 governs lung cancer growth and metastasis by targeting carboxypeptidase-D, DNA Cell Biol., 35, 715-721, doi: https://doi.org/10.1089/dna.2016.3398.

    Article  CAS  PubMed  Google Scholar 

  62. Chandrasekaran, K. S., Sathyanarayanan, A., and Karunagaran, D. (2016) MicroRNA-suppresses growth, migration and invasion through a novel target, high mobility group AT-hook 1, in human cervical and colorectal cancer cells, Br. J. Cancer, 115, 741-751, doi: https://doi.org/10.1038/bjc.2016.234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Das, F., Dey, N., Bera, A., Kasinath, B. S., Ghosh-Choudhury, N., and Choudhury, G. G. (2016) MicroRNA-214 reduces insulin-like growth factor-1 (IGF-1) receptor expression and downstream mTORC1 signaling in renal carcinoma cells, J. Biol. Chem., 291, 14662-14676, doi: https://doi.org/10.1074/jbc.M115.694331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Xia, S. S., Zhang, G. J., Liu, Z. L., Tian, H. P., He, Y., Meng, C. Y., Li, L. F., Wang, Z. W., and Zhou, T. (2017) MicroRNA-22 suppresses the growth, migration and invasion of colorectal cancer cells through a Sp1 negative feedback loop, Oncotarget, 8, 36266-36278, doi: https://doi.org/10.18632/oncotarget.16742.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Dhar, S., Kumar, A., Gomez, C. R., Akhtar, I., Hancock, J. C., Lage, J. M., Pound, C. R., and Levenson, A. S. (2017) MTA1-activated EpimicroRNA-22 regulates E-cadherin and prostate cancer invasiveness, FEBS Lett., 591, 924-933, doi: https://doi.org/10.1002/1873-3468.12603.

    Article  CAS  PubMed  Google Scholar 

  66. Fan, D., Lin, X., Zhang, F., Zhong, W., Hu, J., Chen, Y., Cai, Z., Zou, Y., He, X., Chen, X., Lan, P., and Wu, X. (2018) MicroRNA 26b promotes colorectal cancer metastasis by downregulating phosphatase and tensin homolog and wingless-type MMTV integration site family member 5A, Cancer Sci., 109, 354-362, doi: https://doi.org/10.1111/cas.13451.

    Article  CAS  PubMed  Google Scholar 

  67. Zhang, B., Li, Y., Hou, D., Shi, Q., Yang, S., and Li, Q. (2017) MicroRNA-375 inhibits growth and enhances radiosensitivity in oral squamous cell carcinoma by targeting insulin like growth factor 1 receptor, Cell Physiol. Biochem., 42, 2105-2117, doi: https://doi.org/10.1159/000479913.

    Article  CAS  PubMed  Google Scholar 

  68. Drayton, R. M., Dudziec, E., Peter, S., Bertz, S., Hartmann, A., Bryant, H. E., and Catto, J. W. (2014) Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11, Clin. Cancer Res., 20, 1990-2000, doi: https://doi.org/10.1158/1078-0432.CCR-13-2805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. D’Arcy, M. S. (2019) Cell death: a review of the major forms of apoptosis, necrosis and autophagy, Cell Biol. Int., 43, 582-592, doi: https://doi.org/10.1002/cbin.11137.

    Article  PubMed  Google Scholar 

  70. Franco, R., and Cidlowski, J. A. (2009) Apoptosis and glutathione: beyond an antioxidant, Cell Death Differ., 16, 1303-1314, doi: https://doi.org/10.1038/cdd.2009.107.

    Article  CAS  PubMed  Google Scholar 

  71. Nishizawa, S., Araki, H., Ishikawa, Y., Kitazawa, S., Hata, A., Soga, T., and Hara, T. (2018) Low tumor glutathione level as a sensitivity marker for glutamate-cysteine ligase inhibitors, Oncol. Lett., 15, 8735-8743, doi: https://doi.org/10.3892/ol.2018.8447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Villablanca, J. G., Volchenboum, S. L., Cho, H., Kang, M. H., Cohn, S. L., Anderson, C. P., Marachelian, A., Groshen, S., Tsao-Wei, D., Matthay, K. K., Maris, J. M., Hasenauer, C. E., Czarnecki, S., Lai, H., Goodarzian, F., Shimada, H., and Reynolds, C. P. (2016) A phase I new approaches to neuroblastoma therapy study of buthionine sulfoximine and melphalan with autologous stem cells for recurrent/refractory high-risk neuroblastoma, Pediatr. Blood Cancer, 63, 1349-1356, doi: https://doi.org/10.1002/pbc.25994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tagde, A., Singh, H., Kang, M. H., and Reynolds, C. P. (2014) The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma, Blood Cancer J., 4, 229, doi: https://doi.org/10.1038/bcj.2014.45.

    Article  Google Scholar 

  74. Kittiratphatthana, N., Kukongviriyapan, V., Prawan, A., and Senggunprai, L. (2016) Luteolin induces cholangiocarcinoma cell apoptosis through the mitochondrial-dependent pathway mediated by reactive oxygen species, J. Pharm. Pharmacol., 68, 1184-1192, doi: https://doi.org/10.1111/jphp.12586.

    Article  CAS  PubMed  Google Scholar 

  75. Liu, Y., Liu, T., Lei, T., Zhang, D., Du, S., Girani, L., Qi, D., Lin, C., Tong, R., and Wang Y. (2019) RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (review), Int. J. Mol. Med., 44, 771-786, doi: https://doi.org/10.3892/ijmm.2019.4244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Schwarzer, R., Laurien, L., and Pasparakis, M. (2020) New insights into the regulation of apoptosis, necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8, Curr. Opin. Cell Biol., 63, 186-193, doi: https://doi.org/10.1016/j.ceb.2020.02.004.

    Article  CAS  PubMed  Google Scholar 

  77. Xie, X., Zhao, Y., Ma, C. Y., Xu, X. M., Zhang, Y. Q., Wang, C. G., Jin, J., Shen, X., Gao, J. L., Li, N., Sun, Z. J., and Dong, D. L. (2015) Dimethyl fumarate induces necroptosis in colon cancer cells through GSH depletion/ROS increase/MAPKs activation pathway, Br. J. Pharmacol., 172, 3929-3943, doi: https://doi.org/10.1111/bph.13184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zheng, W., Zhou, C. Y., Zhu, X. Q., Wang, X. J., Li, Z. Y., Chen, X. C., Chen, F., Che, X. Y., and Xie, X. (2018) Oridonin enhances the cytotoxicity of 5-FU in renal carcinoma cells by inducting necroptotic death, Biomed. Pharmacother., 106, 175-182, doi: https://doi.org/10.1016/j.biopha.2018.06.111.

    Article  CAS  PubMed  Google Scholar 

  79. Chauhan, A. K., Min, K. J., and Kwon, T. K. (2017) RIP1-dependent reactive oxygen species production executes artesunate induced cell death in renal carcinoma Caki cells, Mol. Cell. Biochem., 435, 15-24, doi: https://doi.org/10.1007/s11010-017-3052-7.

    Article  CAS  PubMed  Google Scholar 

  80. Chen, M. S., Wang, S. F., Hsu, C. Y., Yin, P. H., Yeh, T. S., Lee, H. C., and Tseng, L. M. (2017) CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway, Oncotarget, 8, 114588-114602, doi: https://doi.org/10.18632/oncotarget.23055.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Lei, P., Bai, T., and Sun, Y. (2019) Mechanisms of ferroptosis and relations with regulated cell death: A review, Front Physiol., 10, 139, doi: https://doi.org/10.3389/fphys.2019.00139.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Ursini, F., and Maiorino, M. (2020) Lipid peroxidation and ferroptosis: the role of GSH and GPx4 (review), Free Radic. Biol. Med., 152, 175-185, doi: https://doi.org/10.1016/j.freeradbiomed.2020.02.027.

    Article  CAS  PubMed  Google Scholar 

  83. Miess, H., Dankworth, B., Gouw, A. M., Rosenfeldt, M., Schmitz, W., Jiang, M., Saunders, B., Howell, M., Downward, J., Felsher, D. W., Peck, B., and Schulze, A. (2018) The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma, Oncogene, 37, 5435-5450, doi: https://doi.org/10.1038/s41388-018-0315-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Seibt, T. M., Proneth, B., and Conrad, M. (2019) Role of GPX4 in ferroptosis and its pharmacological implication, Free Radic. Biol. Med., 133, 144-152, doi: https://doi.org/10.1016/j.freeradbiomed.2018.09.014.

    Article  CAS  PubMed  Google Scholar 

  85. Larraufie, M. H., Yang, W. S., Jiang, E., Thomas, A. G., Slusher, B. S., and Stockwell, B. R. (2015) Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility, Bioorg. Med. Chem. Lett., 25, 4787-4792, doi: https://doi.org/10.1016/j.bmcl.2015.07.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Han, C., Liu, Y., Dai, R., Ismail, N., Su, W., and Li, B. (2020) Ferroptosis and its potential role in human diseases, Front. Pharmacol., 11, 239, doi: https://doi.org/10.3389/fphar.2020.00239.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Shibata, Y., Yasui, H., Higashikawa, K., Miyamoto, N., and Kuge, Y. (2019) Erastin, a ferroptosis-inducing agent, sensitized cancer cells to X-ray irradiation via glutathione starvation in vitro and in vivo, PLoS One, 14, 0225931, doi: https://doi.org/10.1371/journal.pone.0225931.

    Article  CAS  Google Scholar 

  88. Louandre, C., Marcq, I., Bouhlal, H., Lachaier, E., Godin, C., Saidak, Z., Francois, C., Chatelain, D., Debuysscher, V., Barbare, J.-C., Chauffert, B., and Galmiche, A. (2015) The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells, Cancer Lett., 35, 971-977, doi: https://doi.org/10.1016/j.canlet.2014.11.014.

    Article  CAS  Google Scholar 

  89. Cao, S. S., and Kaufman, R. J. (2014) Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease, Antioxid. Redox Signal., 21, 396-413, doi: https://doi.org/10.1089/ars.2014.5851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Guo, J., Xu, B., Han, Q., Zhou, H., Xia, Y., Gong, C., Dai, X., Li, Z., and Wu, G. (2018) Ferroptosis: a novel anti-tumor action for cisplatin, Cancer Res. Treat., 50, 445-460, doi: https://doi.org/10.4143/crt.2016.572.

    Article  CAS  PubMed  Google Scholar 

  91. Dikic, I., Johansen, T., and Kirkin, V. (2010) Selective autophagy in cancer development and therapy, Cancer Res., 70, 3431-3434, doi: https://doi.org/10.1158/0008-5472.CAN-09-4027.

    Article  CAS  PubMed  Google Scholar 

  92. Mancilla, H., Maldonado, R., Cereceda, K., Villarroel-Espindola, F., De Oca, M. M., Angulo, C., Castro, M. A., Slebe, J. C., Vera, J. C., Lavandero, S., and Concha, I. I. (2015) Glutathione depletion induces spermatogonial cell autophagy, J. Cell. Biochem., 116, 2283-2292, doi: https://doi.org/10.1002/jcb.25178.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  94. Desideri, E., Filomeni, G., and Ciriolo, M. R. (2012) Glutathione participates in the modulation of starvation-induced autophagy in carcinoma cells, Autophagy, 8, 1769-1781, doi: https://doi.org/10.4161/auto.22037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Du, J., Wang, T., Li, Y., Zhou, Y., Wang, X., Yu, X., Ren, X., An, Y., Wu, Y., Sun, W., Fan, W., Zhu, Q., Wang, Y., and Tong, X. (2019) DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin, Free Radic. Biol. Med., 131, 356-369, doi: https://doi.org/10.1016/j.freeradbiomed.2018.12.011.

    Article  CAS  PubMed  Google Scholar 

  96. Wu, Z., Geng, Y., Lu, X., Shi, Y., Wu, G., Zhang, M., Shan, B., Pan, H., and Yuan, J. (2019) Chaperone-mediated autophagy is involved in the execution of ferroptosis, Proc. Natl. Acad. Sci. USA, 116, 2996-3005, doi: https://doi.org/10.1073/pnas.1819728116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hou, W., Xie, Y., Song, X., Sun, X., Lotze, M. T., Zeh, H. J., Kang, R., and Tang, D. (2016) Autophagy promotes ferroptosis by degradation of ferritin, Autophagy, 12, 1425-1428, doi: https://doi.org/10.1080/15548627.2016.1187366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gao, M., Monian, P., Pan, Q., Zhang, W., Xiang, J., and Jiang, X. (2016) Ferroptosis is an autophagic cell death process, Cell Res., 26, 1021-1032, doi: https://doi.org/10.1038/cr.2016.95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Santana-Codina, N., and Mancias, J. D. (2018) The role of NCOA4 mediated ferritinophagy in health and disease, Pharmaceuticals, 11, 114-129, doi: https://doi.org/10.3390/ph11040114.

    Article  CAS  PubMed Central  Google Scholar 

  100. Lv, H. H., Zhen, C. X., Liu, J. Y., and Shang, P. (2020) PEITC triggers multiple forms of cell death by GSH-iron-ROS regulation in K7M2 murine osteosarcoma cells, Acta Pharmacol. Sin., 41, 1119-1132, doi: https://doi.org/10.1038/s41401-020-0376-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was financially supported by the Program 5-100 of the Peoples’ Friendship University of Russia.

Author information

Authors and Affiliations

  1. Peoples’ Friendship University of Russia (RUDN University), 117198, Moscow, Russia

    E. V. Kalinina & L. A. Gavriliuk

Authors
  1. E. V. Kalinina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. A. Gavriliuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. V. Kalinina.

Ethics declarations

The authors declare no conflict of interest in financial or any other sphere. This article does not contain any studies with animals or human participants performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kalinina, E.V., Gavriliuk, L.A. Glutathione Synthesis in Cancer Cells. Biochemistry Moscow 85, 895–907 (2020). https://doi.org/10.1134/S0006297920080052

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297920080052

Keywords

Search

Navigation