Background: Eradication of persistent androgen receptor (AR) activity in castration-resistant prostate cancer may be a promising strategy to overcome castration resistance. We aimed to identify novel compounds that inhibit AR activity and could be potential therapeutic agents for prostate cancer. Methods: A high-throughput screening system involving cell lines stably expressing AR protein and AR-responsive luciferase was employed for the 1260 compound library. Molecular and antitumor effects on candidate pathways that interacted with AR signaling were examined in prostate cancer cells expressing AR. Results: The high-throughput screening identified various potential compounds that interfered with AR signaling through known and novel pathways. Among them, a 5-hydroxytryptamine 5A (5-HT5A) receptor antagonist suppressed AR activity through protein kinase A signaling, which was confirmed by 5-HT5A receptor knockdown. Consistently, 5-HT5A receptor inhibitors showed cytotoxic effects toward prostate cancer cells. Conclusions: Taken together, this study identifies 5-HT5A receptor as a promising therapeutic target for prostate cancer via its interaction with AR signaling.
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