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Glutathione S-transferase P influences the Nrf2-dependent response of cellular thiols to seleno-compounds

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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.

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Acknowledgments

Part of this work was produced during the thesis internship of Mrs. Marinelli Rita at Prof. Galli’s Lab.

Funding

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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Author notes

  1. Desirée Bartolini and Daniela Giustarini contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Perugia, Pole of Via del Giochetto, building B, 06126, Perugia, Italy

    Desirée Bartolini, Donatella Pietrella & Francesco Galli

  2. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, I-53100, Siena, Italy

    Daniela Giustarini & Ranieri Rossi

Authors
  1. Desirée Bartolini
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  2. Daniela Giustarini
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  3. Donatella Pietrella
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  4. Ranieri Rossi
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  5. Francesco Galli
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Correspondence to Desirée Bartolini.

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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

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