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PCPH/ENTPD5 Expression Confers to Prostate Cancer Cells Resistance against Cisplatin-Induced Apoptosis through Protein Kinase C–Mediated Bcl-2 Stabilization

¹ Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine, and ² Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia

Requests for reprints: Vicente Notario, Department of Radiation Medicine, Georgetown University Medical Center, Research Building, Room E215, 3970 Reservoir Road Northwest, Washington, DC 20057-1482. Phone: 202-687-2102; Fax: 202-687-2221; E-mail: notariov{at}georgetown.edu.

Key Words: prostate cancer • cisplatin resistance • protein kinase • Bcl-2 • PCPH/mt-PCPH expression

Prostate cancer (PCa) frequently develops antiapoptotic mechanisms and acquires 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 and in PCa, and that the functional interaction between PCPH and protein kinase C (PKC) increases the invasiveness of human PCa. Here, we report that the functional interaction between PCPH and a different PKC isoform, PKC, confers resistance against cisplatin-induced apoptosis to PCa cells. This interaction elicits a mechanism ultimately resulting in the posttranslational stabilization and subsequent elevated expression of Bcl-2. Stable knockdown of either PCPH, mt-PCPH, or PKC in PCa cells decreased Ser70-phosphorylated Bcl-2 and total Bcl-2 protein, thereby increasing their cisplatin sensitivity. Conversely, forced expression of the PCPH protein or, in particular, of the mt-PCPH oncoprotein increased the levels of phosphorylated PKC concurrently with those of Ser70-phosphorylated and total Bcl-2 protein, thus promoting cisplatin resistance. Consistently, Bcl-2 knockdown sensitized PCa cells to cisplatin treatment and, more importantly, reversed the cisplatin resistance of PCa cells expressing the mt-PCPH oncoprotein. Moreover, reexpression of Bcl-2 in PCPH/mt-PCPH knockdown PCa cells reversed the cisplatin 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-PKC-Bcl-2 functional interactions in the drug response process, and imply that targeting PCPH expression before, or simultaneously with, chemotherapy may improve the treatment outcome for PCa patients. [Cancer Res 2009;69(1):102–10]

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