Involvement of Protein Kinase C δ (PKCδ) in Phorbol Ester-induced Apoptosis in LNCaP Prostate Cancer Cells

Fujii, Teruhiko; García‐Bermejo, Maria Laura; Bernabó, Juan Lucas; Caamaño, Jorge H.; Ohba, Masaaki; Kuroki, Toshio; Li, Luowei; Yuspa, Stuart H.; Kazanietz, Marcelo G.

doi:10.1074/jbc.275.11.7574

Cited by 188 publications

(218 citation statements)

References 39 publications

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“…As revealed by the present study, although pretreatment with Gö6976 or bisindolylmaleimide I exerts no significant in previous studies [25,26] . All these results are consistent with our previous findings in human neuroblastoma SH-SY5Y cells [16] , indicating that PKCδ, but not PKCα or the classictype PKC (α, β 1 , β 2 , γ), may play a crucial role in 6-OHDAinduced PC12 cell death.…”

Section: Discussionsupporting

confidence: 59%

Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCδ phosphorylation

et al. 2009

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Objective The present study aims to investigate the role of protein kinase C δ subtype (PKCδ) phosphorylation in the process of 6-hydroxydopamine (6-OHDA)-induced dopaminergic cell death, and demonstrate the molecular basis of neurological disorders, such as Parkinson's disease. Methods The pheochromocytoma (PC12) cell line was employed in the present study. Cells were treated with 2 μmol/L PKCδ inhibitor Rottlerin, 10 nmol/L protein kinase C α subtype (PKCα) inhibitor bisindolylmaleimide I, or 5 nmol/L Gö6976 that could specifically inhibit the calcium-dependent PKC isoforms, respectively. PKCδ activator phorbol-12-myristate-13-acetate (PMA, 100 nmol/L) was also used in this study. All these agents were added to the medium before cells were incubated with 6-OHDA. Cells with no treatment served as control. The cytotoxicity of 6-OHDA was determined by methyl thiazolyl tetrazolium (MTT) reduction assay and PKCδ phosphorylation levels in various groups were measured by western blotting. Results Bisindolylmaleimide I and Gö6976 exerted no significant attenuation on the cytotoxicity of 6-OHDA, nor any effects on PKCδ phosphorylation in PC12 cells. However, Rottlerin could inhibit the phosphorylation of PKCδ and attenuate 6-OHDA-induced cell death, and the cell viability was raised to 69.6±2.63% of that in control group (P < 0.05). In contrast, PMA induced a significant increase in PKCδ phosphorylation and also strengthened the cytotoxic effects of 6-OHDA. The cell viability of PMA-treated PC12 cells decreased to 49.8±5.06% of that in control group (P < 0.001). Conclusion Rottlerin can protect PC12 cells from cytotoxicity of 6-OHDA probably by inhibiting PKCδ phosphorylation. The results suggest that PKCδ may be a key regulator of neuron loss in Parkinson's disease.

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Section: Discussionsupporting

confidence: 59%

Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCδ phosphorylation

et al. 2009

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“…Although the cleavage of PKCy and its catalytic fragment are mainly associated with its proapoptotic effects (9,13,14,30), in some systems PKCy cleavage does not play a role in its apoptotic effects (36,37) or it is associated with PKCy protective effects (24). We found that PKCy-Cyto and PKCy-Mito were cleaved to generate a 40-kDa catalytic fragment.…”

Section: Discussionmentioning

confidence: 72%

The Localization of Protein Kinase Cδ in Different Subcellular Sites Affects Its Proapoptotic and Antiapoptotic Functions and the Activation of Distinct Downstream Signaling Pathways

Gomel

Xiang

Finniss

et al. 2007

Molecular Cancer Research

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Protein kinase CD (PKCD) regulates cell apoptosis and survival in diverse cellular systems. PKCD translocates to different subcellular sites in response to apoptotic stimuli; however, the role of its subcellular localization in its proapoptotic and antiapoptotic functions is just beginning to be understood. Here, we used a PKCD constitutively active mutant targeted to the cytosol, nucleus, mitochondria, and endoplasmic reticulum (ER) and examined whether the subcellular localization of PKCD affects its apoptotic and survival functions. PKCD-Cyto, PKCD-Mito, and PKCD-Nuc induced cell apoptosis, whereas no apoptosis was observed with the PKCD-ER. PKCD-Cyto and PKCD-Mito underwent cleavage, whereas no cleavage was observed in the PKCD-Nuc and PKCD-ER. Similarly, caspase-3 activity was increased in cells overexpressing PKCD-Cyto and PKCD-Mito. In contrast to the apoptotic effects of the PKCD-Cyto, PKCD-Mito, and PKCD-Nuc, the PKCD-ER protected the cells from tumor necrosis factor -related apoptosis-inducing ligand -induced and etoposideinduced apoptosis. Moreover, overexpression of a PKCD kinase-dead mutant targeted to the ER abrogated the protective effect of the endogenous PKCD and increased tumor necrosis factor -related apoptosis-inducing ligand -induced apoptosis. The localization of PKCD differentially affected the activation of downstream signaling pathways. PKCD-Cyto increased the phosphorylation of p38 and decreased the phosphorylation of AKT and the expression of X-linked inhibitor of apoptosis protein, whereas PKCD-Nuc increased c-Jun NH 2 -terminal kinase phosphorylation. Moreover, p38 phosphorylation and the decrease in X-linked inhibitor of apoptosis protein expression played a role in the apoptotic effect of PKCD-Cyto, whereas c-Jun NH 2 -terminal kinase activation mediated the apoptotic effect of PKCD-Nuc. Our results indicate that the subcellular localization of PKCD plays important roles in its proapoptotic and antiapoptotic functions and in the activation of downstream signaling pathways.

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“…Previous studies suggested that upregulation of c-Jun (Gaynor et al, 1991), tumour necrosis factor a (TNF a) (Takada et al, 1999), or protein kinase C (PKC) b (Kaneki et al, 1999) might play an important role in the induction of differentiation and cell growth arrest in these cells. In addition, TPA was shown to induce apoptosis in LNCaP, an androgensensitive human prostate cancer cell line through the upregulation of PKC-d (Fujii et al, 2000), -a (Garzotto et al, 1998), or ceramide synthesis (Powell et al, 1996). Other studies also showed that TPA upregulated the expression of p21 waf1 and downregulated the levels of c-Myc as growth of LNCaP cells slowed (Mitchell and El-Deiry, 1999).…”

mentioning

confidence: 99%

JNK interacting protein 1 (JIP-1) protects LNCaP prostate cancer cells from growth arrest and apoptosis mediated by 12-0-tetradecanoylphorbol-13-acetate (TPA)

et al. 2004

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Involvement of Protein Kinase C δ (PKCδ) in Phorbol Ester-induced Apoptosis in LNCaP Prostate Cancer Cells

Cited by 188 publications

References 39 publications

Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCδ phosphorylation

Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCδ phosphorylation

The Localization of Protein Kinase Cδ in Different Subcellular Sites Affects Its Proapoptotic and Antiapoptotic Functions and the Activation of Distinct Downstream Signaling Pathways

JNK interacting protein 1 (JIP-1) protects LNCaP prostate cancer cells from growth arrest and apoptosis mediated by 12-0-tetradecanoylphorbol-13-acetate (TPA)

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