Molecular analysis of anti-androgenic effects of atraric acid on human prostate cancer in vivo and androgen receptor-mediated negative regulation of the TERT gene
Prostate cancer (PCa) is a major health concern of men in Western countries. At initial phases the tumor depends on androgens therefore, androgen ablation became an essential therapy of PCa. After first being successful, the treatment eventually fails and tumors progress to the more aggressive form of the disease called castration-resistant prostate cancer (CRPC). Since the androgen receptor (AR) was reported to have growth promoting as well as tumor suppressive activities, and remains to be expressed in CRPC, the failure of therapy is not simply attributed to a loss of AR function. A deeper understanding of molecular mechanisms of processes involved and the identification of the mode of action of novel AR antagonists may help to optimize targeted PCa growth inhibition. One of the AR target genes is the catalytic subunit of the human telomerase, TERT. In the present study it could be demonstrated that the AR mediates TERT gene activation as well as repression depending on cellular context. Hence, TERT as a single AR target reflects the contrasting effects of androgen signaling. The AR-mediated regulation of TERT expression was functionally analyzed. Thereby, a small AR-responsive region was identified within the proximal TERT promoter, which is repressed in a ligand-dependent manner. It was demonstrated that AR antagonists, like the natural compound atraric acid, which inhibits the growth of CRPC cells, do not block AR-mediated gene repression of the TERT gene while inhibiting AR-dependent transactivation. Furthermore, a murine xenograft model of CRPC revealed that atraric acid inhibits the growth of human prostate tumors in vivo. Analyzing the tumors suggests that a molecular signaling pathway, which is targeted by the treatment, is the pRB signaling axis. Interestingly, signaling molecules involved in this pathway are frequently affected in advanced PCa specimens strengthening the potency of atraric acid as a novel AR antagonist.