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

Alakananda Basu, Giridhar Rao Akkaraju

Research output: Contribution to journalArticle

Abstract

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
JournalBiochemistry
Volume38
Issue number14
DOIs
StatePublished - 6 Apr 1999

Fingerprint

Cell death
Caspases
Protein Kinase C
Cisplatin
Cell Death
Caspase 3
Chemical activation
Caspase 7
Isoenzymes
Down-Regulation
Caspase 2
Caspase 1
Poly(ADP-ribose) Polymerases
Antineoplastic Agents
Signal Transduction
Signal transduction
Peptide Hydrolases
bryostatin 1
Apoptosis

Cite this

@article{618ae31a50d640cd8fe66e1bfe3a131d,
title = "Regulation of caspase activation and cis-diamminedichloroplatinum(II)- induced cell death by protein kinase C",
abstract = "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.",
author = "Alakananda Basu and Akkaraju, {Giridhar Rao}",
year = "1999",
month = "4",
day = "6",
doi = "10.1021/bi982854q",
language = "English",
volume = "38",
pages = "4245--4251",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "14",

}

Regulation of caspase activation and cis-diamminedichloroplatinum(II)- induced cell death by protein kinase C. / Basu, Alakananda; Akkaraju, Giridhar Rao.

In: Biochemistry, Vol. 38, No. 14, 06.04.1999, p. 4245-4251.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Regulation of caspase activation and cis-diamminedichloroplatinum(II)- induced cell death by protein kinase C

AU - Basu, Alakananda

AU - Akkaraju, Giridhar Rao

PY - 1999/4/6

Y1 - 1999/4/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033528718&partnerID=8YFLogxK

U2 - 10.1021/bi982854q

DO - 10.1021/bi982854q

M3 - Article

C2 - 10194341

VL - 38

SP - 4245

EP - 4251

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 14

ER -