Protein kinase C as a molecular target for cancer prevention by selenocompounds.

Selenium is a very effective cancer-preventive agent, suppressing tumor promotion and early stages of tumor progression. However, the mechanisms by which selenium exerts these cancer-preventive actions are not known. Protein kinase C (PKC) is a receptor for certain tumor promoters and also plays a crucial role in events related to tumor progression. Therefore, it is not only a potential target for the cancer-preventive activity of selenium, but also it has the structural basis for interaction with selenium. Redox-active selenocompounds can inactivate PKC, particularly the Ca(2+)-dependent isozymes, by reacting with the critical cysteine-rich regions present within the catalytic domain while, in some cases, also reacting with the cysteine residues present within the zinc-fingers of the regulatory domain. The selenoprotein thioredoxin reductase (TR), acting through thioredoxin, reverses the inactivation of PKC induced by selenometabolites. Furthermore, TR, through a direct interaction involving its selenosulfur center with the zinc-thiolates of PKC, can reverse the redox modification of this kinase induced by selenometabolites. Thus the selenometabolite-induced toxicity is reversed by a selenoprotein, and therefore an interrelationship exists between these two mechanisms of selenium actions. Moreover, this also explains how a resistance to selenium develops in advanced tumor cells probably due to an overexpression of functional TR. Selenium-induced inactivation of PKC may, at least in part, be responsible for the selenium-induced inhibition of tumor promotion, cell growth, invasion, and metastasis, as well as for the induction of apoptosis.