Regulation of caspase activation and cis-diamminedichloroplatinum(II)- induced cell death by protein kinase C

Alakananda Basu, Giridhar Rao Akkaraju

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84 Scopus citations


Activation of caspases is critical for the induction of apoptosis. We have shown previously that cell death mediated by the anticancer agent cis- diamminedichloroplatinum(II) (cDDP) is influenced by the protein kinase C (PKC) signal transduction pathway. In the present study, we have examined whether regulation of cDDP sensitivity by PKC involves caspase activation, cDDP caused a time- and concentration-dependent increase in the generation of the catalytic fragment (CF) of novel (n) PKCδ, nPKCε, and atypical (a) PKCζ but had little effect on conventional (c) PKCα. Cleavage of PKC isozymes was associated with the activation of caspase-3 and -7 but not of caspase-2. PKC activators enhanced cDDP-induced cleavage of these isozymes and activation of caspase-3. Rottlerin, an inhibitor of nPKCδ, blocked caspase-3 activation and proteolytic cleavage of nPKCδ by cDDP. Bryostatin 1, which elicits a biphasic concentration-response in potentiating cell death by cDDP, exhibited a similar biphasic effect on cDDP-induced activation of caspase-3 and caspase-7 and the cleavage of poly(ADP-ribose) polymerase; while 1 nM bryostatin 1 induced maximum activation of these caspases, 1 μM bryostatin 1 had little effect, z-DEVD-fmk, an inhibitor of caspase-3-like proteases, prevented cDDP-induced cell death. Bryostatin 1 also induced a similar biphasic down-regulation of nPKCδ but not of cPKCα or nPKCε. These results suggest that nPKCδ not only acts downstream of caspases but also regulates the activation of caspases and that the biphasic concentration response of bryostatin 1 on cDDP-induced cell death could be explained by its distinct effect on nPKCδ down-regulation and caspase activation.

Original languageEnglish
Pages (from-to)4245-4251
Number of pages7
Issue number14
StatePublished - 6 Apr 1999


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