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Chemosensitization of Androgen-Independent Prostate Cancer with Neutral Endopeptidase

¹Department of Urology, National Defense Medical College, Tokorozawa, Saitama, Japan, and² Urologic Oncology Research Laboratory, Department of Urology and the Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York

Purpose: We investigated whether neutral endopeptidase (NEP) could augment chemosensitivity to anticancer drugs by promoting protein kinase C (PKC)-mediated mitochondrial apoptosis in prostate cancer (PC) cells.

Experimental Design: Human PC cell lines LNCaP and PC-3, and a normal prostate epithelial cell line (PrEC) were used. The protein expression was detected by Western blot analysis, and the protein turnover was determined by pulse-chase assay. Apoptotic ratio was measured by annexin V staining.

Results: Western blot analyses and pulse-chase assays showed that the specific NEP inhibitor CGS24592 decreased PKC protein expression by promoting PKC protein degradation in NEP-expressing LNCaP cells. Conversely, recombinant NEP (rNEP) increased PKC protein expression by delaying PKC protein degradation in NEP-negative PC-3 cells. Apoptosis assays showed that rNEP promoted anticancer drug-induced apoptosis in PC-3 cells specifically through PKC activity that mediated anticancer drug-induced mitochondrial change such as cytochrome-c release and caspase-9 activation. Of note, rNEP was able to increase PKC protein expression predominantly in PC-3 cells rather than in PrEC cells. Treatment with rNEP before subtoxic concentrations of etoposide (0.1 µM) significantly promoted mitochondrial apoptosis compared with only etoposide in PC-3 cells (P < 0.01) but not in PrEC cells.

Conclusions: These results suggest that NEP enzyme activity contributes to anticancer drug-induced PC cell apoptosis dependent on PKC-mediated mitochondrial events. More importantly, the combination of NEP with anticancer drugs may be a promising therapeutic modality because rNEP is able to augment chemosensitivity in androgen-independent PC with minimal toxicity in normal tissues.

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