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

被引:33
作者
Villar, Joaquin [1 ]
Quadri, Humair S. [1 ]
Song, Insun [2 ]
Tomita, York [2 ]
Tirado, Oscar M. [1 ]
Notario, Vicente [1 ]
机构
[1] Georgetown Univ, Med Ctr, Dept Radiat Med, Expt Carcinogenesis Lab, Washington, DC 20057 USA
[2] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20057 USA
关键词
PCPH PROTOONCOGENE; DEREGULATED EXPRESSION; PHOSPHORYLATION; INHIBITION; DELTA; SURVIVAL; FAMILY; CPH; INVOLVEMENT; PROGRESSION;
D O I
10.1158/0008-5472.CAN-08-2922
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 delta (PKC delta) increases the invasiveness of human PCa. Here, we report that the functional interaction between PCPH and a different PKC isoform, PKC alpha, 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 alpha 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 alpha 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 alpha-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]
引用
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页码:102 / 110
页数:9
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