V-ATPase-dependent repression of androgen receptor in prostate cancer cells

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Prostate cancer (PCa) is a leading cause of cancer death in men.
• Suppressing androgen receptor (AR) is a key strategy for PCa management.
• V-adenosine triphosphatase (V-ATPase) role in PCa progression needs further elucidation.

Purpose of the Study:

• To investigate the effect of V-ATPase inhibition on AR expression in PCa cells.
• To elucidate the molecular mechanisms underlying V-ATPase-mediated AR regulation.
• To explore the role of HIF-1α in the V-ATPase-AR signaling axis.

Main Methods:

• Treatment of PCa cell lines (LAPC4, LNCaP) with V-ATPase inhibitor concanamycin A (CCA).
• Analysis of AR and PSA mRNA levels.
• Assessment of HIF-1α protein levels, hydroxylation, and nuclear localization.
• Investigation of iron's role in modulating HIF-1α and AR expression.

Main Results:

• CCA treatment significantly reduced AR expression and PSA mRNA levels in PCa cells.
• CCA disrupted endo-lysosomal pH regulation, leading to transcriptional repression of AR.
• CCA increased HIF-1α protein levels by inhibiting its hydroxylation and degradation.
• Iron supplementation partially reversed CCA-induced AR repression and normalized HIF-1α levels.
• DMOG confirmed HIF-1α as a downstream mediator in the V-ATPase-AR pathway.

Conclusions:

• V-ATPase inhibition represents a novel strategy to suppress AR expression in prostate cancer.
• Defective endosomal iron trafficking and subsequent HIF-1α stabilization are key mechanisms.
• This study uncovers a new V-ATPase-dependent pathway regulating AR in PCa.