Regulation of Caspase Activation and <i>cis</i>-Diamminedichloroplatinum(II)-Induced Cell Death by Protein Kinase C

Basu, Alakananda; Akkaraju, Giridhar R.

doi:10.1021/bi982854q

Cited by 76 publications

(71 citation statements)

References 23 publications

(47 reference statements)

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“…19,20 We have provided evidence that the PKC signal transduction pathway in fact acts upstream of caspase-3. 17 The results of the present study demonstrate that in HeLa cells PKCd is constitutively associated with the HM fraction containing mitochondria and cisplatin induced proteolytic activation of PKCd in both fractions. Furthermore, while inhibition of PKCd only partially influences cDDP-induced Cytochrome c release, it inhibits cDDP-induced activation of caspases in both the cytosol and mitochondria.…”

Section: Discussionsupporting

confidence: 56%

“…Immunoblot analyses were performed as described before. 17 Intensities of immunoreactive proteins were quantified by laser densitometry. In each experiment, the same blot was probed with several antibodies to account for any loading differences.…”

Section: Immunoblot Analysismentioning

confidence: 99%

“…19,20 We have, however, demonstrated that downregulation of PKC that decreased the abundance of PKCd catalytic fragment was associated with increased cellular sensitivity to cDDP. 17 These results raise the possibility that PKC acts upstream of caspases to regulate cell death by cDDP. It is not known which PKC isozyme regulates activation of caspases and which step(s) of the cisplatin-induced cell death pathway is regulated by PKC.…”

Section: Introductionmentioning

confidence: 98%

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Involvement of protein kinase C-δ in DNA damage-induced apoptosis

2001

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We have previously shown that the protein kinase C (PKC) signal transduction pathway regulates cell death by the DNA damaging agent cis-diamminedichloroplatinum(II) (cDDP). In the present study we have investigated how PKC influences the sequence of events that are triggered by cDDP-induced DNA damage. cDDP caused activation of caspases-8, -9, -3, -7 and cleavage of PKCd. Rottlerin, a selective inhibitor of novel PKCd, blocked activation of caspases, proteolytic activation of PKCd and cell death induced by cDDP. In contrast, Go È 6976, an inhibitor of conventional PKCa and bI, did not prevent cDDP-induced caspase activation and cDDP cytotoxicity. In HeLa cells, PKCd was distributed both in the cytosol and heavy membrane (HM) fraction containing mitochondria. While caspase-8 was primarily cytosolic, a small amount of caspases-9, -7 and -3 could be detected in the HM fraction. cDDP caused a time-dependent increase in Cytochrome c release from the mitochondria and processing of both cytosolic and membrane-associated caspases, as well as proteolytic cleavage of PKCd. Rottlerin attenuated late but not early release of Cytochrome c by cDDP. It, however, inhibited activation of caspases and proteolytic cleavage of PKCd in both cytosolic and HM fractions. The antiapoptotic effect of rottlerin was evident when it was added together with or following cDDP addition but not when added after cDDP was removed from the medium. Thus, the PKCd inhibitor acts at an early stage of the cDDP-induced cell death pathway that precedes caspase activation. Cell Death and Differentiation (2001) 8, 899 ± 908.

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Section: Discussionsupporting

confidence: 56%

Section: Immunoblot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Involvement of protein kinase C-δ in DNA damage-induced apoptosis

2001

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“…Our data are not, however, inconsistent with the possibility that PKC might be regulating only caspase-8 and exerting a consequent inhibitory effect in downstream caspases. A recent report describes a PKC-dependent inhibition of caspase-3 activity in apoptosis induced by cisdiamminedichloroplatinum(II) in HeLa cells (91), but no mechanism is proposed in the study. Moreover, it should be mentioned that there are divergences between the anti and proapoptotic effects of PKC shown in the literature that seem to be dependent on cell type, apoptotic stimulus, and the PKC isotype considered.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C (PKC) Inhibits Fas Receptor-induced Apoptosis through Modulation of the Loss of K+ and Cell Shrinkage

Gómez‐Angelats

Bortner

Cidlowski

2000

Journal of Biological Chemistry

120

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in whole cell extracts from anti-Fas treated Jurkat T cells. However, stimulation of PKC by PMA or bryostatin-1 prevented this isotypic-specific PKC cleavage during apoptosis, providing further evidence that PKC itself exerts an upstream signal in apoptosis and controls the caspase-dependent proteolytic degradation of PKC isotypes. Finally, we show that PMA or bryostatin-1 prevents the activation of caspase-3 and caspase-8. Thus, this study shows that the protective effect that PKC stimulation exerts in the Fas-mediated apoptotic pathway occurs at a site upstream of caspases-3 and -8.During apoptosis, cells activate an intrinsic death program that eventually eliminates them from the surrounding cells in a process that in vivo reduces the likelihood of an inflammatory response. Apoptosis induced by ligation of the cell surface Fas/ Apo1/CD95 receptor (1-4) plays a pivotal role in the physiological turnover of lymphoid cells, which dysfunction can lead to an overgrowth of lymphoid organs and to a variety of disease states (5). Studies on cell death induced by activation of the well defined Fas receptor system have indeed provided extensive information on the cellular and molecular bases of apoptosis. Cell death mediated by Fas receptor (for review, see Refs. 6 -8) is the result of the initiation and transmission of cellular signals that activate the inherent cell death machinery, which ultimately leads to the disassembly of the cell in a highly regulated process. In this context, activation of the Fas receptor by the Fas ligand molecule or anti-Fas antibody sequentially induces clustering and trimerization of the receptor, followed by its interaction with Fas-associated death domain (FADD) adaptor protein and subsequent recruitment of caspase-8 to the Fas receptor complex, which leads to the formation of deathinducing signaling complex (DISC) 1 (9), and initiates the activation of the caspase pathway (10 -12).From lymphocytes to neurons, an incipient mark of apoptotic cells is their shrunken morphology (13-19). However, the cellular mechanisms involved in apoptotic cell shrinkage are not well understood. The maintenance of cell volume is an energydemanding process, the failure of which dramatically challenges cell function. During apoptosis, cells follow a program which success is dependent on many cellular functions that are required to fully complete the entire apoptotic cascade. Hence, this early apoptotic loss of cell volume has been proposed to be an active regulated process required for the apoptotic progression. Our laboratory and others have demonstrated that cell shrinkage and the loss of intracellular K ϩ are early and necessary features of apoptosis (13,14,19,20). In fact, in a total cell population forced to die by an apoptotic stimulus, only the shrunken/low intracellular [K ϩ ] cells show characteristics of apoptosis, i.e. DNA degradation and effector caspase activation (19). Activation of effector caspases plays a key role in the hierarchy of the cell death cascade (21). Caspase-8 is the most p...

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“…Proteolytic activation of PKC␦ by caspases is a common event during apoptosis, and expression of its isolated catalytic domain induces apoptosis (4,5). This cofactor-independent activation of PKC␦ further activates caspase-3 and function as a positive feedback loop (6,7). However, in breast cancer, the role of PKC␦ is more ambiguous.…”

mentioning

confidence: 99%

Protein Kinase Cδ Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway

Lønne

Masoumi

Lennartsson

et al. 2009

Journal of Biological Chemistry

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Mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer. Protein kinase C␦ (PKC␦) is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. Here, we report for the first time that down-regulation of PKC␦ per se leads to apoptosis of MDA-MB-231 cells. Inhibition of MEK1/2 by either PD98059 or U0126 suppressed the induction of apoptosis of PKC␦-depleted MDA-MB-231 cells but did not support survival of MCF-7 or MDA-MB-468 cells. Basal ERK1/2 phosphorylation was substantially higher in MDA-MB-231 cells than in the other cell lines. PKC␦ depletion led to even higher ERK1/2 phosphorylation levels and also to lower expression levels of the ERK1/2 phosphatase MKP3. Depletion of MKP3 led to apoptosis and higher levels of ERK1/2 phosphorylation, suggesting that this may be a mechanism mediating the effect of PKC␦ down-regulation. However, PKC␦ silencing also induced increased MEK1/2 phosphorylation, indicating that PKC␦ regulates ERK1/2 phosphorylation both upstream and downstream. Moreover, PKC␦ silencing led to increased levels of the E3 ubiquitin ligase Nedd4, which is a potential regulator of MKP3, because down-regulation led to increased MKP3 levels. Our results highlight PKC␦ as a potential target for therapy of breast cancers with high activity of the ERK1/2 pathway.

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Regulation of Caspase Activation and cis-Diamminedichloroplatinum(II)-Induced Cell Death by Protein Kinase C

Cited by 76 publications

References 23 publications

Involvement of protein kinase C-δ in DNA damage-induced apoptosis

Involvement of protein kinase C-δ in DNA damage-induced apoptosis

Protein Kinase C (PKC) Inhibits Fas Receptor-induced Apoptosis through Modulation of the Loss of K+ and Cell Shrinkage

Protein Kinase Cδ Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway

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