Androgen blocks apoptosis of hormone-dependent prostate cancer cells

Androgen plays a critical role in the promotion and growth of prostate canc er. Androgen ablation has an expanding role in prostate cancer treatment an d is now used to improve the efficacy of radiation therapy in addition to i ts role in treatment of metastatic disease. Here we show that androgen inte rferes with induction of prostate cancer cell death induced by a variety of stimuli. The effect of androgen on cell death occurs predominantly by inte rference with caspase activation and the inhibition of caspase cleavage in both the extrinsic and intrinsic cell death pathways, Androgen inhibited ap optosis induced by both tumor necrosis factor alpha (TNF-alpha) and by Fas activation with or without concomitant irradiation, An antiapoptotic effect was seen in the presence of R1881, dihydrotestosterone, and also 17 beta - estradiol within 24 h of death induction. Sustained inhibition of apoptosis at 72 h was seen only with R1881, dihydrotestosterone, cyproterone acetate , and hydroxyflutamide. Androgen treatment inhibited activation of caspases -8, -7, and -9 by TNF-alpha +/- irradiation. Androgen attenuated BAX expres sion and blocked appearance of the proapoptotic pig fragment of BAX, Androg en also abrogated BID cleavage induced by TNF-alpha + irradiation that cont ributed to a decrease in cytochrome c egress from mitochondria induced by T NF-alpha +/- irradiation. There was also decreased mitochondrial depolariza tion in response to TNF-alpha + irradiation, Production of the proapoptotic lipid metabolite ceramide was not affected by androgen, but androgen acted downstream from ceramide generation because R1881 blocked cell-death induc tion by bacterial sphingomyelinase. Inhibition of phosphoinositol-3-kinase activity by wortmannin induced apoptosis that was also blocked by androgen, but there was no effect on protein levels or phosphorylation of AKT, indic ating that R1881 did not interact with survival signaling of phosphoinosito l-3-kinase, Lastly, androgen inhibited activation of nuclear factor-kappaB during death induction, but the effect of androgen on cell death was not me diated by interference with the nuclear factor-kappaB pathway. The data sug gest that androgen induced blockade of caspase activation in both intrinsic and extrinsic cell death pathways and thereby was able to protect prostate cancer cells from apoptosis induced by diverse stimuli.