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Neutral Endopeptidase Promotes Phorbol Ester-induced Apoptosis in Prostate Cancer Cells by Inhibiting Neuropeptide-induced Protein Kinase C Degradation¹

Urologic Oncology Research Laboratory, Department of Urology [M. S., R. S., J. D, D. N., D. M. N.], and the Division of Hematology and Medical Oncology, Department of Medicine [J. S. G., D. M. N.], Joan and Stanford I. Weill Medical College of Cornell University, New York, New York 10021

Phorbol esters induce apoptosis in androgen-sensitive LNCaP cells, which express neutral endopeptidase (NEP), but not in androgen-independent prostate cancer (PC) cells, which lack NEP expression. We investigated the role of NEP in PC cell susceptibility to 12-O-tetradecanoylphorbol-13-acetate (TPA). Western analysis showed that expression of NEP and protein kinase C (PKC) correlated with PC cell sensitivity to TPA-induced growth arrest and apoptosis in LNCaP cells and in TSU-Pr1 cells expressing an inducible wild-type NEP protein. Inhibition of NEP enzyme activity using the specific NEP inhibitor CGS24592, or inhibition of PKC using Rottlerin at concentrations that inhibit PKC but not PKC, significantly inhibited TPA-induced growth inhibition and cell death. Furthermore, pulse-chase experiments showed PKC is stabilized in LNCaP cells and in TSU-Pr1 cells overexpressing wild-type NEP compared with PC cells lacking NEP expression. This results from NEP inactivation of its neuropeptide substrates (bombesin and endothelin-1), which in the absence of NEP stimulate cSrc kinase activity and induce rapid degradation of PKC protein. These results indicate that expression of enzymatically active NEP by PC cells is necessary for TPA-induced apoptosis, and that NEP inhibits neuropeptide-induced, cSrc-mediated PKC degradation.

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