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Interruption of Nuclear Factor B Signaling by the Androgen Receptor Facilitates 12-O-Tetradecanoylphorbolacetate-Induced Apoptosis in Androgen-sensitive Prostate Cancer LNCaP Cells

George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, University of Rochester Medical Center, Rochester, New York 14642 [S. A., H-K. L., K-H. C., S. Y., W-J. L., L. A. H., M. M. R., L. Y., Y. Z., C. C.], and Graduate Institute of Clinical Medical Sciences and Center for Menopause and Reproductive Medicine Research, Chang Gung University, Taiwan 833, Republic of China [H-Y. K., M-Y. T.]

12-O-tetradecanoylphorbolacetate (TPA) influences proliferation, differentiation, and apoptosis in a variety of cells including prostate cancer cells. Here, we show that androgen treatment potentiates TPA-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells but not in androgen-independent prostate cancer cell lines DU145 and PC-3. The use of the antiandrogen bicalutamide (Casodex) rescued LNCaP cells from 5--dihydrotestosterone (DHT)/TPA-induced apoptosis, suggesting that DHT/TPA-induced apoptosis is mediated by androgen/androgen receptor (AR). In addition, a caspase-3 inhibitor (Ac-DEVD-CHO) reduced the level of apoptosis, suggesting that DHT/TPA-mediated apoptosis occurs through a caspase-3-dependent pathway. A functional reporter assay using nuclear factor (NF) B-luciferase and an electromobility gel shift assay showed that DHT suppressed NFB activity. In addition, apoptosis mediated by combined DHT/TPA treatment was abrogated by overexpression of the NFB subunit p65 in LNCaP-p65 cells, suggesting that NFB may play an important role in regulating the effects of androgen/AR and TPA on apoptosis. Furthermore, use of the c-Jun N-terminal kinase (JNK) inhibitor SB202190 showed that the combination of DHT/TPA increased JNK activation in LNCaP cells but not in LNCaP-p65 cells, demonstrating that NFB may be able to suppress JNK activity. These results indicate that androgen/AR facilitates TPA-induced apoptosis by interruption of the NFB signaling pathway, leading to activation of JNK in LNCaP cells. These data describe a signaling pathway that could potentially be useful in proposed therapeutic treatment strategies exploiting combinations of different agents that control apoptosis in prostate tumors.

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