Regulation of Caspase Activation and cis-Diamminedichloroplatinum(II)-Induced Cell Death by Protein Kinase C
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- 作者：Alakananda Basu and Giridhar Rao Akkaraju
- 刊名：Biochemistry
- 出版年：1999
- 出版时间：April 6, 1999
- 年：1999
- 卷：38
- 期：14
- 页码：4245 - 4251
- 全文大小：120K
- 年卷期：v.38,no.14(April 6, 1999)
- ISSN：1520-4995
文摘
Activation of caspases is critical for the induction of apoptosis. We have shown previouslythat cell death mediated by the anticancer agent cis-diamminedichloroplatinum(II) (cDDP) is influencedby the protein kinase C (PKC) signal transduction pathway. In the present study, we have examinedwhether regulation of cDDP sensitivity by PKC involves caspase activation. cDDP caused a time- andconcentration-dependent increase in the generation of the catalytic fragment (CF) of novel (n) PKC
,nPKC
, and atypical (a) PKC
but had little effect on conventional (c) PKC
. Cleavage of PKC isozymeswas associated with the activation of caspase-3 and -7 but not of caspase-2. PKC activators enhancedcDDP-induced cleavage of these isozymes and activation of caspase-3. Rottlerin, an inhibitor of nPKC,blocked caspase-3 activation and proteolytic cleavage of nPKC by cDDP. Bryostatin 1, which elicits abiphasic concentration-response in potentiating cell death by cDDP, exhibited a similar biphasic effect oncDDP-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 
M bryostatin 1 had littleeffect. z-DEVD-fmk, an inhibitor of caspase-3-like proteases, prevented cDDP-induced cell death. Bryostatin1 also induced a similar biphasic down-regulation of nPKC but not of cPKC or nPKC. These resultssuggest that nPKC not only acts downstream of caspases but also regulates the activation of caspasesand that the biphasic concentration response of bryostatin 1 on cDDP-induced cell death could be explainedby its distinct effect on nPKC down-regulation and caspase activation.
,nPKC, and atypical (a) PKC but had little effect on conventional (c) PKC. Cleavage of PKC isozymeswas associated with the activation of caspase-3 and -7 but not of caspase-2. PKC activators enhancedcDDP-induced cleavage of these isozymes and activation of caspase-3. Rottlerin, an inhibitor of nPKC,blocked caspase-3 activation and proteolytic cleavage of nPKC by cDDP. Bryostatin 1, which elicits abiphasic concentration-response in potentiating cell death by cDDP, exhibited a similar biphasic effect oncDDP-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 M bryostatin 1 had littleeffect. z-DEVD-fmk, an inhibitor of caspase-3-like proteases, prevented cDDP-induced cell death. Bryostatin1 also induced a similar biphasic down-regulation of nPKC but not of cPKC or nPKC. These resultssuggest that nPKC not only acts downstream of caspases but also regulates the activation of caspasesand that the biphasic concentration response of bryostatin 1 on cDDP-induced cell death could be explainedby its distinct effect on nPKC down-regulation and caspase activation.