High-throughput screen identifies 5-HT receptor as a modulator of AR and a therapeutic target for prostate cancer

Momoe Itsumi; Masaki Shiota; Yohei Sekino; Miho Ushijima; Eiji Kashiwagi; Ario Takeuchi; Junichi Inokuchi; Shunichi Kajioka; Takeshi Uchiumi; Masatoshi Eto

doi:10.1002/pros.24022

High-throughput screen identifies 5-HT receptor as a modulator of AR and a therapeutic target for prostate cancer

Momoe Itsumi, Masaki Shiota, Yohei Sekino, Miho Ushijima, Eiji Kashiwagi, Ario Takeuchi, Junichi Inokuchi, Shunichi Kajioka, Takeshi Uchiumi, Masatoshi Eto

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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.

Original language	English
Pages (from-to)	885-894
Number of pages	10
Journal	Prostate
Volume	80
Issue number	11
DOIs	https://doi.org/10.1002/pros.24022
Publication status	Published - Aug 1 2020

All Science Journal Classification (ASJC) codes

Oncology
Urology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/pros.24022

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title = "High-throughput screen identifies 5-HT receptor as a modulator of AR and a therapeutic target for prostate cancer",

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.",

keywords = "5-hydroxytryptamine receptor, androgen receptor, high-throughput screen, prostate cancer, protein kinase A",

author = "Momoe Itsumi and Masaki Shiota and Yohei Sekino and Miho Ushijima and Eiji Kashiwagi and Ario Takeuchi and Junichi Inokuchi and Shunichi Kajioka and Takeshi Uchiumi and Masatoshi Eto",

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year = "2020",

month = aug,

day = "1",

doi = "10.1002/pros.24022",

language = "English",

volume = "80",

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T1 - High-throughput screen identifies 5-HT receptor as a modulator of AR and a therapeutic target for prostate cancer

AU - Itsumi, Momoe

AU - Shiota, Masaki

AU - Sekino, Yohei

AU - Ushijima, Miho

AU - Kashiwagi, Eiji

AU - Takeuchi, Ario

AU - Inokuchi, Junichi

AU - Kajioka, Shunichi

AU - Uchiumi, Takeshi

AU - Eto, Masatoshi

PY - 2020/8/1

Y1 - 2020/8/1

N2 - 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.

AB - 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.

KW - 5-hydroxytryptamine receptor

KW - androgen receptor

KW - high-throughput screen

KW - prostate cancer

KW - protein kinase A

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JO - Prostate

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ER -

High-throughput screen identifies 5-HT receptor as a modulator of AR and a therapeutic target for prostate cancer

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