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We reported previously that cystine produces regulatory responses in purified, recombinant human protein kinase C-delta (PKCdelta) and PKCepsilon via S-thiolation-triggered mechanisms that are consistent with a cancer preventive effect, i.e. stimulation of the pro-apoptotic, tumor-suppressive isozyme PKCdelta and inactivation of the growth-stimulatory, oncogenic isozyme PKCepsilon, at S-cysteinylation stoichiometries that correspond to modification of a single redox-regulatory cysteine (Cys) switch in each isozyme. In this report, we show that the oxidative regulatory responses of purified PKCdelta and PKCepsilon to cystine are recapitulated in disulfide-treated cells. We report that treatment of COS7-PKCepsilon transfectants with the cystine precursor cystine dimethyl ester (CDME) produced concentration- and time-dependent PKCepsilon inactivation that was associated with oxidative PKCepsilon modification manifested as attenuated band intensity in PKCepsilon immunoblot analyses, and that both PKCepsilon inactivation and modification were reversed by dithiothreitol (DTT) as well as by thioredoxin. We also show that CDME induced biphasic PKCdelta regulation in COS7-PKCdelta transfectants, with DTT-irreversible PKCdelta stimulation at low and DTT-reversible PKCdelta inactivation at high CDME concentrations. The degrees of PKCdelta versus PKCepsilon inactivation by CDME treatment of COS7-PKC transfectants indicate substantial resistance of PKCdelta to inactivation. The PKCdelta stimulatory response in COS7-PKCdelta cells was triggered only by the disulfide agent and not by its reduced thiol counterpart, providing evidence for an oxidative mechanism. Also paralleling the oxidative stimulation of purified PKCdelta by cystine, the stimulation of PKCdelta elicited by CDME treatment of cells involved a stable structural change, which was evident from the stability of the stimulated form of PKCdelta to immunoprecipitation. Demonstration of oxidative regulation of cellular PKCdelta and PKCepsilon by disulfides in this report provides evidence that redox-regulatory sites in PKCdelta and PKCepsilon may offer novel targets for development of cancer preventive or therapeutic agents that selectively inactivate PKCepsilon or stimulate PKCdelta.

carcinogenesis

Cellular protein kinase C isozyme regulation by exogenously delivered physiological disulfides--implications of oxidative protein kinase C regulation to cancer prevention