Metformin exerts anti-AR-negative prostate cancer activity via AMPK/autophagy signaling pathway

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Prostate cancer remains a significant health challenge, necessitating novel treatment strategies.
• Androgen receptor-negative (AR-negative) prostate cancer presents unique therapeutic challenges.
• Metformin's potential anti-cancer effects are under investigation.

Purpose of the Study:

• To elucidate the mechanism by which metformin inhibits AR-negative prostate cancer growth.
• To investigate the role of autophagy and cell cycle regulation in metformin's anti-cancer effects.
• To evaluate the therapeutic potential of targeting the AMPK/autophagy pathway.

Main Methods:

• Utilized DU145 and PC3 cell lines to assess cell proliferation, cell cycle, and autophagy.
• Employed CCK8 assays, colony formation, scratch tests, and flow cytometry.
• Conducted Western blot analysis, immunofluorescence for LC3B, and siRNA-mediated AMPK knockdown.
• Evaluated metformin's efficacy in a tumor formation xenograft model in vivo.

Main Results:

• Metformin significantly inhibited prostate cancer cell proliferation and induced G0/G1 cell cycle arrest.
• Metformin treatment activated AMP-activated protein kinase (AMPK) and promoted autophagy, evidenced by increased LC3II and decreased p62/SQSTM1.
• In vivo studies demonstrated reduced tumor volume and suppressed proliferation marker Ki-67 with metformin treatment, alongside elevated p-AMPK and LC3B levels.

Conclusions:

• Autophagy induction is a key mechanism underlying metformin's suppression of AR-negative prostate cancer.
• The activation of the AMPK/autophagy pathway represents a promising therapeutic strategy for AR-negative prostate cancer.
• Metformin's anti-cancer effects are mediated through modulation of cellular processes including autophagy and cell cycle progression.