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.
Gopalakrishna
R
R
Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. rgopalak@hsc.usc.edu
Gundimeda
U
U
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000737:chemistry* / Q000378:metabolism*; D018036:Selenium Compounds / Q000627:therapeutic use*
D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D018036:Selenium Compounds; D011493:Protein Kinase C; D002118:Calcium