NDLI: PCPH/ENTPD5 expression confers to prostate cancer cells resistance against cisplatin-induced apoptosis through PKCα-mediated Bcl-2 stabilization

Content Provider	PubMed Central
Author	Villar, Joaquín Quadri, Humair S. Song, Insun Tomita, York Tirado, Oscar M. Notario, Vicente
Abstract	Prostate cancer (PCa) frequently develops anti-apoptotic mechanisms and acquire resistance to anticancer drugs. Therefore, identifying PCa drug resistance determinants should facilitate designing more effective chemotherapeutic regimens. Recently, we described that the PCPH protein becomes highly expressed in human prostatic intraepithelial neoplasia (PIN) and in PCa, and that the functional interaction between PCPH and protein kinase Cδ (PKCδ) increases the invasiveness of human PCa. Here, we report that the functional interaction between PCPH and a different PKC isoform, PKCα, confers resistance against cisplatin (Cp)-induced apoptosis to PCa cells. This interaction elicits a mechanism ultimately resulting in the post-translational stabilization and subsequent elevated expression of Bcl-2. Stable knockdown of either PCPH, mt-PCPH or PKCα in PCa cells decreased Ser70-phosphorylated Bcl-2 and total Bcl-2 protein, thereby increasing their Cp sensitivity. Conversely, forced expression of the PCPH protein or, in particular, of the mt-PCPH oncoprotein increased the levels of phosphorylated PKCα concurrently with those of Ser70-phosphorylated and total Bcl-2 protein, thus promoting Cp resistance. Consistently, Bcl-2 knockdown sensitized PCa cells to Cp treatment and, more importantly, reversed the Cp resistance of PCa cells expressing the mt-PCPH oncoprotein. Moreover, re-expression of Bcl-2 in PCPH/mt-PCPH knocked-down PCa cells reversed the Cp sensitization caused by PCPH or mt-PCPH down-regulation. These findings identify PCPH and mt-PCPH as important participants in the chemotherapy response of PCa cells, establish a role for PCPH-PKCα-Bcl-2 functional interactions in the drug response process, and imply that targeting PCPH expression prior to, or simultaneously with, chemotherapy may improve the treatment outcome for PCa patients.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-08-2922
Ending Page	110
Page Count	9
Starting Page	102
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	1
Volume Number	69
Language	English
Publisher Date	2009-01-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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