thapsigargin and bicalutamide

Androgen deprivation induces the regression of prostate tumors mainly due to an increase in the apoptosis rate; however, the molecular mechanisms underlying the antiapoptotic actions of androgens are not completely understood. We have studied the antiapoptotic effects of androgens in prostate cancer cells exposed to different proapoptotic stimuli. Terminal deoxynucleotidyl transferase-mediated nick-end labeling and nuclear fragmentation analyses demonstrated that androgens protect LNCaP prostate cancer cells from apoptosis induced by thapsigargin, the phorbol ester 12-O-tetradecanoyl-13-phorbol-acetate, or UV irradiation. These three stimuli require the activation of the c-Jun N-terminal kinase (JNK) pathway to induce apoptosis and in all three cases, androgen treatment blocks JNK activation. Interestingly, okadaic acid, a phosphatase inhibitor that causes apoptosis in LNCaP cells, induces JNK activation that is also inhibited by androgens. Actinomycin D, the antiandrogen bicalutamide or specific androgen receptor (AR) knockdown by small interfering RNA all blocked the inhibition of JNK activation mediated by androgens indicating that this activity requires AR-dependent transcriptional activation. These data suggest that the crosstalk between AR and JNK pathways may have important implications in prostate cancer progression and may provide targets for the development of new therapies.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Anilides; Apoptosis; Down-Regulation; Enzyme Activation; Humans; In Situ Nick-End Labeling; JNK Mitogen-Activated Protein Kinases; Male; Microscopy, Fluorescence; Neoplasms, Hormone-Dependent; Nitriles; Prostatic Neoplasms; Receptors, Androgen; RNA, Small Interfering; Tetradecanoylphorbol Acetate; Thapsigargin; Tosyl Compounds; Tumor Cells, Cultured; Ultraviolet Rays