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PCPH/ENTPD5 Expression Enhances the Invasiveness of Human Prostate Cancer Cells by a Protein Kinase C–Dependent Mechanism

¹ Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia and ² Department of Cell Biology and Genetics, University of Alcalá, Alcalá de Henares, Madrid, Spain

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

Previous reports showed that PCPH is mutated or deregulated in some human tumors, suggesting its participation in malignant progression. Immunohistochemical analyses showed that PCPH is not expressed in normal prostate, but its expression increases along cancer progression stages, being detectable in benign prostatic hyperplasia, highly expressed in prostatic intraepithelial neoplasia, and remaining at high levels in prostate carcinoma. Experiments designed to investigate the contribution of PCPH to the malignant phenotype of prostate cancer cells showed that PCPH overexpression in PC-3 cells, which express nearly undetectable PCPH levels, increased collagen I expression and enhanced invasiveness, whereas shRNA-mediated PCPH knockdown in LNCaP cells, which express high PCPH levels, down-regulated collagen I expression and decreased invasiveness. PCPH regulated invasiveness and collagen I expression by a mechanism involving protein kinase C (PKC): (a) PCPH knockdown in LNCaP cells decreased PKC levels relative to control cells; (b) PKC knockdown in LNCaP cells recapitulated all changes caused by PCPH knockdown; and (c) forced expression of PKC in cells with knocked down PCPH reverted all changes provoked by PCPH down-regulation and rescued the original phenotype of LNCaP cells. These results strongly suggested that the expression level and/or mutational status of PCPH contributes to determine the invasiveness of prostate cancer cells through a mechanism involving PKC. Data from immunohistochemical analyses in serial sections of normal, premalignant, and malignant prostate specimens underscored the clinical significance of our findings by showing remarkably similar patterns of expression for PCPH and PKC, thus strongly suggesting their likely coregulation in human tumors. [Cancer Res 2007;67(22):10859–68]