Inhibition of androgen receptor and β-catenin activity in prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Androgen receptor (AR) is a key target in prostate cancer, but resistance develops.
• Simultaneous targeting of multiple pathways offers a promising therapeutic strategy.
• β-catenin signaling is frequently dysregulated in prostate cancer.

Purpose of the Study:

• To investigate the efficacy of a small-molecule inhibitor (C3) targeting nuclear β-catenin activity.
• To determine if C3 can simultaneously inhibit AR and β-catenin signaling pathways in prostate cancer.
• To provide proof-of-concept for a dual-targeting approach in prostate cancer treatment.

Main Methods:

• Utilized a small-molecule inhibitor (C3) targeting nuclear β-catenin.
• Assessed disruption of β-catenin/T-cell factor and β-catenin/AR protein interactions.
• Evaluated effects on AR promoter occupancy, gene expression, and in vivo tumor growth in xenograft models.

Main Results:

• C3 treatment inhibited prostate cancer cell growth by disrupting key protein interactions.
• Decreased β-catenin occupancy on the AR promoter and reduced AR target gene expression were observed.
• C3 inhibited tumor growth in vivo and prevented the proliferation of resistant cells.

Conclusions:

• C3 effectively inhibits both AR and β-catenin signaling, offering a novel therapeutic strategy for prostate cancer.
• The findings highlight an unrecognized role of β-catenin in regulating AR function.
• C3 demonstrates significant therapeutic potential for aggressive and resistant prostate cancer.