Androgen receptor-mTOR crosstalk is regulated by testosterone availability: Implication for prostate cancer cell survival

Background: Signaling between androgen receptor (AR) and mTOR may be crucial for prostate cancer cells to endure the low androgen and suboptimal nutrient conditions produced by androgen deprivation therapy. Materials and Methods: AR and mTOR cross-talk was examined in LNCaP cells exposed to either high or low testosterone. AR and mTOR activities were modified separately using either siRNA knockdown or specific chemical inhibitor. The biological significance of the reciprocal communication was assessed by susceptibility to glucose deprivation-induced cell death. Results: AR positively regulated mTOR activity in both low and high testosterone levels. TSC1 and TSC2, the two negative regulators of mTOR, may be involved since both were up-regulated by AR knockdown. Sub-baseline mTOR increased AR protein levels. However, this effect only occurred with low testosterone. More cells underwent apoptosis if AR function was inhibited during glucose deprivation, which significantly depressed mTOR activity. Conclusion: The compensatory increase of AR function due to a repressed mTOR signal is advantageous for survival. Disrupting this loop at the time of initiation of androgen deprivation therapy may delay, or even prevent, the recurrence of prostate cancer.