Redox regulation of protein kinase C by selenometabolites and selenoprotein thioredoxin reductase limits cancer prevention by selenium

Free Radical Biology & Medicine
Rayudu GopalakrishnaA Holmgren

Abstract

The cancer-preventive mechanism of selenium should address the way low concentrations of selenometabolites react with cellular targets without being diffused from the sites of generation, the way selenium selectively kills tumor cells, and the intriguing U-shaped curve that is seen with dietary supplementation of selenium and cancer prevention. Protein kinase C (PKC), a receptor for tumor promoters, is well suited for this mechanism. Due to the catalytic redox cycle, low concentrations of methylselenol, a postulated active metabolite of selenium, react with the tumor-promoting lipid hydroperoxide bound to PKC to form methylseleninic acid (MSA), which selectively reacts with thiol residues present within the vicinity of the PKC catalytic domain to inactivate it. Given that lipid hydroperoxide levels are high in promoting cells, PKC inactivation selectively leads to death in these cells. A biphasic effect of MSA in inducing cell death was observed in certain prostate cancer cell lines; lower concentrations of MSA induced cell death, while higher concentrations failed to do so. Lower concentrations of selenium inactivate more sensitive antiapoptotic isoenzymes of PKC (ε and α), sparing less sensitive proapoptotic isoenzymes (PKCδ ...Continue Reading

Citations

Apr 2, 2021·Archives of Toxicology·Cristina W NogueiraJoão B T Rocha
Sep 30, 2020·Redox Biology·Jinsong ZhangMargaret P Rayman

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