Antioxidant Regulation of Protein Kinase C in Cancer Prevention

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Abstract
Besides scavenging free radicals, antioxidants inhibit signaling enzymes such as protein kinase C (PKC) that play a crucial role in tumor promotion. By having different oxidation susceptible regions, PKC can respond to both oxidant tumor promoters and cancer-preventive antioxidants to elicit opposite cellular responses. Oxidant tumor promoters activate PKC by reacting with zinc-thiolates present within the regulatory domain. In contrast, the oxidized forms of some cancer-preventive agents, such as polyphenolics (ellagic acid, 4-hydroxytamoxifen and curcumin) and selenocompounds, can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. This brings an efficient counteractive mechanism to block the signal transduction induced by tumor promoters at the first step itself. Because prostate cancer prevention clinical trials in large human population are under way, we have focused more on understanding the cancer-preventive mechanism of selenium. Methylselenol, the postulated cancer-preventive metabolite, has no direct effect on PKC activity. However, methylseleninic acid, locally generated by the reaction of membrane methylselenol with PKC-bound tumor-promoting fatty acid hydroperoxides, selectively inactivates PKC. This mechanism clarifies how the volatile methylselenol that is present in a low concentration induces the inactivation of PKC selectively in the promoting precancer cells. Selenoprotein thioredoxin reductase reverses selenium-induced inactivation of PKC, suggesting that selenoproteins may serve as a safeguard against the toxicity induced by selenometabolites. Moreover, this also explains how a resistance to selenium develops in advanced malignant cells. The redox-mediated inactivation of PKC may, at least in part, be responsible for the antioxidant-induced inhibition of tumor promotion and cell growth, as well as for the induction of cell death.