The Impact of Indoles Activating the Aryl Hydrocarbon Receptor on Androgen Receptor Activity in the 22Rv1 Prostate...

Area of Science:

• Pharmacology
• Molecular Biology
• Oncology

Background:

• Prostate cancer (PCa) is often androgen receptor (AR)-dependent, making AR a key therapeutic target.
• Xenobiotic activation of the aryl hydrocarbon receptor (AhR) can lead to androgen receptor (AR) degradation.
• Bacterial mimicry suggests potential therapeutic applications for compounds targeting AR activity.

Purpose of the Study:

• To investigate whether indole compounds activating AhR can restrict AR activity in prostate cancer cells.
• To explore the mechanism by which indoles affect AR signaling and expression.

Main Methods:

• Screening of 22 indolic compounds for AhR activation and AR activity suppression.
• Measurement of AR luciferase activity and DHT-inducible gene expression (KLK3, FKBP5).
• Chromatin immunoprecipitation (ChIP) assay to assess AR binding to the KLK3 promoter.
• CRISPR/Cas9 technology to knockout AhR and evaluate its role.

Main Results:

• All 22 tested indoles activated AhR; eight suppressed DHT-induced AR luciferase activity.
• Indoles meeting both criteria reduced KLK3 and FKBP5 mRNA expression and AR promoter binding.
• Some indoles decreased AR protein and mRNA levels.
• AhR knockout did not correlate with changes in AR target gene expression, suggesting an AhR-independent mechanism.

Conclusions:

• Certain AhR-activating indoles exhibit AR-inhibiting activity in prostate cancer cells.
• This inhibition appears to be primarily through downregulation of AR expression, not solely degradation.
• The study found no direct link between AhR activation and AR activity suppression in 22Rv1 cells, indicating a complex interaction.