This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sumitomo, M. Articles by Nanus, D. M. Search for Related Content PubMed PubMed Citation Articles by Sumitomo, M. Articles by Nanus, D. M.

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.

This article has been cited by other articles:

				J. Gong, J. Lee, H. Akio, P. N. Schlegel, and R. Shen Attenuation of Apoptosis by Chromogranin A-Induced Akt and Survivin Pathways in Prostate Cancer Cells Endocrinology, September 1, 2007; 148(9): 4489 - 4499. [Abstract] [Full Text] [PDF]

				H. F. Valenzuela, K. E. Pace, P. V. Cabrera, R. White, K. Porvari, H. Kaija, P. Vihko, and L. G. Baum O-Glycosylation Regulates LNCaP Prostate Cancer Cell Susceptibility to Apoptosis Induced by Galectin-1 Cancer Res., July 1, 2007; 67(13): 6155 - 6162. [Abstract] [Full Text] [PDF]

				H. Kajiyama, K. Shibata, M. Terauchi, T. Morita, K. Ino, S. Mizutani, and F. Kikkawa Neutral Endopeptidase 24.11/CD10 Suppresses Progressive Potential in Ovarian Carcinoma In vitro and In vivo Clin. Cancer Res., March 1, 2005; 11(5): 1798 - 1808. [Abstract] [Full Text] [PDF]

				L. Yin, N. Bennani-Baiti, and C. T. Powell Phorbol Ester-induced Apoptosis of C4-2 Cells Requires Both a Unique and a Redundant Protein Kinase C Signaling Pathway J. Biol. Chem., February 18, 2005; 280(7): 5533 - 5541. [Abstract] [Full Text] [PDF]

				J. Asakuma, M. Sumitomo, T. Asano, T. Asano, and M. Hayakawa Selective Akt Inactivation and Tumor Necrosis Factor-related Apoptosis-inducing Ligand Sensitization of Renal Cancer Cells by Low Concentrations of Paclitaxel Cancer Res., March 15, 2003; 63(6): 1365 - 1370. [Abstract] [Full Text] [PDF]

				M. Sumitomo, M. I. Milowsky, R. Shen, D. Navarro, J. Dai, T. Asano, M. Hayakawa, and D. M. Nanus Neutral Endopeptidase Inhibits Neuropeptide-mediated Transactivation of the Insulin-like Growth Factor Receptor-Akt Cell Survival Pathway Cancer Res., April 1, 2001; 61(8): 3294 - 3298. [Abstract] [Full Text]