Abstract
Recent findings suggest a functional interaction of the drug resistance enzyme glutathione S-transferase P (GSTP) with the transcription factor Nrf2, a master regulator of the adaptive stress response to cellular electrophiles. The effect of this interaction on the metabolism and redox of cellular thiols was investigated in this study during the exposure to alkylating Se-compounds in murine embryonic fibroblasts (MEFs). GSTP1-1 gene ablation was confirmed to upregulate Nrf2 activity and to increase Cys uptake and the de novo biosynthesis of reduced glutathione (GSH) that was readily released in the extracellular medium together with other cellular thiols. This latter response was associated with a higher expression of the membrane transporter MRP1 and was markedly stimulated by the treatment with alkylating Se-compounds together with protein S-glutathionylation that was observed to be under the influence of GSTP expression. The response of cellular thiols to Se-compounds was not altered by the transient (SiRNA-induced) or stable inactivation of NRF2 in GSTP competent or hGSTP1 transfected cells, while defects of GSH biosynthesis, efflux, and redox were observed after NRF2 silencing in GSTP−/− MEFs. In conclusion, GSTP is confirmed to functionally interact with Nrf2 and to have a prominent position in the pecking order of factors that control both the Nrf2-dependent and independent response of cellular thiols to alkylating agents.
References
Bartolini D, Commodi J, Piroddi M, Incipini L, Sancineto L, Santi C, et al. Glutathione S-transferase pi expression regulates the Nrf2-dependent response to hormetic diselenides. Free Radic Biol Med. 2015a;88(Pt B):466–80.
Bartolini D, Piroddi M, Tidei C, Giovagnoli S, Pietrella D, Manevich Y, et al. Reaction kinetics and targeting to cellular glutathione S-transferase of the glutathione peroxidase mimetic PhSeZnCl and its D,L-polylactide microparticle formulation. Free Radic Biol Med. 2015b;78:56–65.
Bartolini D, Torquato P, Piroddi M, Galli F. Targeting glutathione S-transferase P and its interactome with selenium compounds in cancer therapy. Biochim Biophys Acta Gen Subj. 2019a;1863(1):130–43.
Bartolini D, Wang Y, Zhang J, Giustarini D, Rossi R, Wang GY, et al. A seleno-hormetine protects bone marrow hematopoietic cells against ionizing radiation-induced toxicities. PLoS One. 2019b;14(4):e0205626.
Carvalho AN, Marques C, Guedes RC, Castro-Caldas M, Rodrigues E, van Horssen J, et al. S-Glutathionylation of Keap1: a new role for glutathione S-transferase pi in neuronal protection. FEBS Lett. 2016;590(10):1455–66.
Colombo G, Dalle-Donne I, Orioli M, Giustarini D, Rossi R, Clerici M, et al. Oxidative damage in human gingival fibroblasts exposed to cigarette smoke. Free Radic Biol Med. 2012;52(9):1584–96.
Danyelle M, Townsend YM, He L, Hutchens S, Pazoles CJ, Tew KD. Novel role for glutathione S-transferase Pi. Regulator of proteins S-glutathionylation following oxidative and nitrosative stress. J Biol Chem. 2008:436–45.
De Nicola M, Ghibelli L. Glutathione depletion in survival and apoptotic pathways. Front Pharmacol. 2014;5:267.
Habib E, Linher-Melville K, Lin HX, 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.
Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005;45:51–88.
Henderson CJ, McLaren AW, Wolf CR. In vivo regulation of human glutathione transferase GSTP by chemopreventive agents. Cancer Res. 2014;74(16):4378–87.
Higgins LG, Hayes JD. Mechanisms of induction of cytosolic and microsomal glutathione transferase (GST) genes by xenobiotics and pro-inflammatory agents. Drug Metab Rev. 2011;43(2):92–137.
Ji L, Li H, Gao P, Shang G, Zhang DD, Zhang N, et al. Nrf2 pathway regulates multidrug-resistance-associated protein 1 in small cell lung cancer. PLoS One. 2013;8(5):e63404.
Jones JT, Qian X, van der Velden JL, Chia SB, McMillan DH, Flemer S, et al. Glutathione S-transferase pi modulates NF-kappaB activation and pro-inflammatory responses in lung epithelial cells. Redox Biol. 2016;8:375–82.
Nikawa T, Schuch G, Wagner G, Sies H. Interaction of ebselen with glutathione S-transferase and papain in vitro. Biochem Pharmacol. 1994a;47(6):1007–12.
Nikawa T, Schuch G, Wagner G, Sies H. Interaction of albumin-bound ebselen with rat liver glutathione S-transferase and microsomal proteins. Biochem Mol Biol Int. 1994b;32(2):291–8.
Olm E, Fernandes AP, Hebert C, Rundlof AK, Larsen EH, Danielsson O, et al. Extracellular thiol-assisted selenium uptake dependent on the x(c)- cystine transporter explains the cancer-specific cytotoxicity of selenite. Proc Natl Acad Sci U S A. 2009;106(27):11400–5.
Scire A, Cianfruglia L, Minnelli C, Bartolini D, Torquato P, Principato G, et al. Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways. Biofactors. 2019;45(2):152–68.
Sivandzade F, Prasad S, Bhalerao A, Cucullo L. NRF2 and NF-B interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches. Redox Biol. 2019;21:101059.
Tebay LE, Robertson H, Durant ST, Vitale SR, Penning TM, Dinkova-Kostova AT, et al. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med. 2015;88(Pt B):108–46.
Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res. 1994;54(16):4313–20.
Waxman DJ. Glutathione S-transferases: role in alkylating agent resistance and possible target for modulation chemotherapy--a review. Cancer Res. 1990;50(20):6449–54.
Ye ZW, Zhang J, Ancrum T, Manevich Y, Townsend DM, Tew KD. Glutathione S-Transferase P-mediated protein S-Glutathionylation of resident endoplasmic reticulum proteins influences sensitivity to drug-induced unfolded protein response. Antioxid Redox Signal. 2017;26(6):247–61.
Acknowledgments
Part of this work was produced during the thesis internship of Mrs. Marinelli Rita at Prof. Galli’s Lab.
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DB is a postdoctoral fellow funded by the grant program “Piano di Sviluppo Rurale” of the Umbria Region, Italy (VISTA project).
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Bartolini, D., Giustarini, D., Pietrella, D. et al. Glutathione S-transferase P influences the Nrf2-dependent response of cellular thiols to seleno-compounds. Cell Biol Toxicol 36, 379–386 (2020). https://doi.org/10.1007/s10565-020-09517-5
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DOI: https://doi.org/10.1007/s10565-020-09517-5