Selenium compounds are substrates for glutaredoxins: A novel pathway for selenium metabolism and a potential mechanism for selenium mediated cytotoxicity
Résumé
The glutaredoxins (Grx) are oxidoreductases with a central function in maintaining the redox balance within the cell. In this study we have explored the reactions between selenium compounds and the glutaredoxin system. Selenite, selenodiglutathione and selenocystine were all shown to be substrates to human Grx1, implying a novel role for the glutaredoxins in selenium metabolism. During the last years, selenium has further evolved as a potential therapeutic agent in cancer treatment and a leading mechanism of cytotoxicity is generation of reactive oxygen species (ROS). Both selenite and selenodiglutathione were reduced by Grx1 and Grx2 in a non stoichiometric manner, due to redox cycling with oxygen, which in turn generated ROS. The role of Grx in selenium toxicity was therefore explored. Cells were treated with the selenium compounds in combination with transient overexpression and siRNA for Grx1. The results demonstrated an increased viability of the cells during silencing of Grx1, indicating that Grx1 is contributing to selenium toxicity. This is in contrast to thioredoxin reductase (TrxR), which previously was shown to protect cells from selenium cytotoxicity, verifying a diverse role between Grx and TrxR in selenium mediated cytotoxicity. Furthermore, selenium treatment led to a marked increase in protein glutathionylation and cysteinylation that potentially can influence the activity and function of several proteins within the cell.
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