Carcinogenesis, Vol. 22, No. 8, 1221-1229,
August 2001
© 2001 Oxford University Press
CARCINOGENESIS |
Potent inactivation of representative members of each PKC isozyme subfamily and PKD via S-thiolation by the tumor-promotion/progression antagonist glutathione but not by its precursor cysteine
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 173, Houston, TX 77030, USA
We recently established that S-glutathiolation of cPKC
fully inactivates the isozyme, at a stoichiometry of ~1 mol GSH/mol cPKC. In this report we demonstrate that, in addition to cPKC, six other PKC isozymes that are representative of the three subfamilies within the PKC family (cPKCß1, cPKCß2 and cPKC
, nPKC
and nPKC
and aPKC-
) are subject to inactivation by S-glutathiolation induced by the thiol-specific oxidant diamide, which induces disulfide bridge formation. Among PKD and the seven PKC isozymes examined in this report only nPKC has been directly implicated as an antagonist of tumor promotion/progression, while several of the kinases have been implicated in the mediation of tumor promotion/progression. We report that of the kinases examined nPKC was the most resistant to inactivation by diamide-induced S-glutathiolation. In the absence of GSH only nPKC activity exhibited a biphasic response to diamide, with low diamide concentrations oxidatively enhancing nPKC activity and higher concentrations inactivating the isozyme; the other seven kinases were subject to monophasic, concentration-dependent, oxidative inactivation by diamide to various extents. The results provide evidence that at least some pro-oxidant environments may support the potent inactivation of nPKC and other PKC isozymes implicated in tumor promotion/progression by the mechanisms of S-glutathiolation and, in some cases, disulfide bridge formation among the isozyme thiols, without inducing substantial nPKC inactivation. The results also show that neither the seven PKC isozymes examined nor PKD are inactivated by S-cysteinylation under conditions that support potent inactivation by S-glutathiolation. This indicates that the protection that the tumor promotion/progression antagonist GSH may afford against oxidative tumor promotion/progression mechanisms by S-thiolating and inactivating PKC isozymes and PKD cannot be afforded by the metabolic GSH precursor cysteine. These observations support a role for PKC inactivation via S-glutathiolation in the mechanism of tumor promotion/progression antagonism by GSH in pro-oxidant environments.
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