PKC sulfhydryl targeting by disulfiram produces divergent isozymic regulatory responses that accord with the cancer preventive activity of the thiuram disulfide.
The protein kinase C (PKC) isozyme family plays key roles in cell growth regulation and influences neoplastic disease development and progression. For example, PKCepsilon is oncogenic, and PKCdelta tumor-suppressive. PKC isozymes are characterized by distinct activation mechanisms entailing phosphatidylserine-dependent cofactor binding to the regulatory domain. Evidence is now emerging that redox signaling offers another platform of PKC regulation. We have established that PKC isozymes are regulated by S-thiolation, a posttranslational modification entailing disulfide linkage of low-molecular-weight species to select protein sulfhydryls. Our recent studies demonstrate that physiologically occurring disulfides with cysteinyl constituents, e.g., cystine, regulate cellular PKC isozymes by S-thiolation-triggered mechanisms. This report shows that PKC isozymes are also molecular targets of a chemically distinct class of disulfides. Disulfiram is a thiuram disulfide with potent cancer preventive activity in in vivo models of chemical carcinogenesis. Our results indicate that PKC Sthiolation by disulfiram induces differential regulatory effects on PKC isozymes that correlate with the cancer preventive activity of the drug. The implication of these findings is that PKC-regulatory effects of thiuram disulfides may offer a useful pharmacological guide for development of disulfiram analogues with superior cancer preventive activity.
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Feng
F
Chu
Catherine A
CA
O'Brian
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004220:Disulfides / Q000378:metabolism*; D004221:Disulfiram / Q000737:chemistry* / Q000494:pharmacology*; D004229:Dithiothreitol / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005609:Free Radicals; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D011493:Protein Kinase C / Q000302:isolation & purification / Q000378:metabolism*; D013893:Thiram / Q000494:pharmacology*
D004220:Disulfides; D005609:Free Radicals; D007527:Isoenzymes; D013893:Thiram; D011493:Protein Kinase C; D004229:Dithiothreitol; D004221:Disulfiram