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Updated: Dec 20, 2025
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
High-throughput screen identifies 5-HT receptor as a modulator of AR and a therapeutic target for prostate cancer
Momoe Itsumi1, Masaki Shiota1, Yohei Sekino2
1Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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.
Insights
Researchers identified a new way to fight prostate cancer by targeting the 5-hydroxytryptamine 5A (5-HT5A) receptor. This discovery offers a potential new therapeutic strategy for castration-resistant prostate cancer by inhibiting androgen receptor (AR) activity.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgen receptor (AR) activity is a key driver in prostate cancer progression.
- Overcoming castration resistance requires targeting persistent AR activity.
- Identifying novel inhibitors of AR signaling is crucial for developing new prostate cancer therapies.
Purpose of the Study:
- To identify novel compounds that inhibit androgen receptor (AR) activity.
- To explore potential therapeutic agents for castration-resistant prostate cancer.
- To investigate new pathways involved in AR signaling.
Main Methods:
- Utilized a high-throughput screening system with AR-expressing cell lines and AR-responsive luciferase.
- Screened a library of 1260 compounds for AR activity inhibitors.
- Examined molecular and antitumor effects of candidate compounds on AR signaling pathways.
Main Results:
- Identified compounds interfering with AR signaling through known and novel pathways.
- A 5-hydroxytryptamine 5A (5-HT5A) receptor antagonist was found to suppress AR activity via protein kinase A signaling.
- 5-HT5A receptor inhibitors demonstrated cytotoxic effects on prostate cancer cells.
Conclusions:
- The 5-hydroxytryptamine 5A (5-HT5A) receptor is a promising therapeutic target for prostate cancer.
- Targeting the 5-HT5A receptor can inhibit AR signaling.
- This research provides a novel strategy for treating castration-resistant prostate cancer.
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