High‐throughput screen identifies 5‐HT receptor as a modulator of AR and a therapeutic target for prostate cancer. Issue 11 (1st June 2020)

• Record Type: Journal Article
• Authors: Itsumi, Momoe; Shiota, Masaki; Sekino, Yohei; Ushijima, Miho; Kashiwagi, Eiji; Takeuchi, Ario; Inokuchi, Junichi; Kajioka, Shunichi; Uchiumi, Takeshi; Eto, Masatoshi
• Is Part Of: Prostate. Volume 80:Issue 11(2020)
• Page Start: 885
• Page End: 894
• Publication Date: 2020-06-01
• Subjects: 5‐hydroxytryptamine receptor -- androgen receptor -- high‐throughput screen -- prostate cancer -- protein kinase A; Prostate -- Diseases -- Periodicals; 616
• DOI: 10.1002/pros.24022
• Languages: English
• ISSNs: 0270-4137

Abstract

Abstract: 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.