Inhibiting Multiple Deubiquitinases to Reduce Androgen Receptor Expression in Prostate Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Prostate cancer (PCa) is a leading cause of cancer death in men.
• Castration-resistant PCa (CRPC) develops resistance to androgen deprivation therapy by increasing androgen receptor (AR) activity.
• Enzalutamide, an AR inhibitor, improves survival but resistance emerges rapidly.

Purpose of the Study:

• To investigate betulinic acid (BA) as an adjuvant therapy for CRPC.
• To determine if BA reduces AR expression and selectively kills PCa cells.
• To explore the potential of multi-deubiquitinase (DUB) inhibitors in CRPC treatment.

Main Methods:

• Investigated the effect of BA on AR protein stability and mRNA expression in PCa cells.
• Assessed the mechanism of BA-induced AR mRNA reduction, involving histone 2A DUB inhibition.
• Identified specific DUBs inhibited by BA and WP1130 in PCa cells and using recombinant DUBs.

Main Results:

• BA reduced AR protein stability and mRNA expression in PCa cells.
• BA's mechanism may involve inhibiting histone 2A DUB, leading to increased ubiquitinated histone 2A.
• Both BA and WP1130, multi-DUB inhibitors, decreased AR expression and increased PCa-specific cell death.

Conclusions:

• Betulinic acid (BA) shows potential as an agent to decrease AR expression in CRPC.
• Multi-DUB inhibitors like BA and WP1130 can reduce AR expression and induce PCa cell death.
• Combining BA or WP1130 with enzalutamide may offer a novel therapeutic strategy for CRPC by enhancing AR downregulation and apoptosis.