FOXM1 contributes to docetaxel resistance in castration-resistant prostate cancer by inducing AMPK/mTOR-mediated...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Docetaxel is a primary treatment for metastatic castration-resistant prostate cancer (CRPC).
• Therapeutic efficacy of docetaxel is often limited by acquired drug resistance.
• The role of Forkhead box protein M1 (FOXM1) in docetaxel resistance remains uninvestigated.

Purpose of the Study:

• To investigate the role of FOXM1 in docetaxel resistance in CRPC.
• To elucidate the underlying molecular mechanisms, including the involvement of autophagy.
• To explore potential therapeutic strategies targeting FOXM1 and autophagy.

Main Methods:

• Utilized docetaxel-resistant CRPC cell lines (PC3-DR, VCaP-DR) and in vivo models.
• Assessed FOXM1 expression levels and its functional impact via knockdown and overexpression studies.
• Investigated autophagy flux, autophagosome formation, and the role of autophagy-related genes (ATG7, beclin-1).
• Examined the effect of chloroquine, an autophagy inhibitor, on docetaxel sensitivity.
• Analyzed the mechanistic link between FOXM1, AMPK/mTOR pathway, and autophagy activation.

Main Results:

• FOXM1 expression was significantly upregulated in docetaxel-resistant CRPC cells.
• FOXM1 knockdown sensitized resistant cells to docetaxel in vitro and in vivo.
• Autophagy was markedly enhanced in resistant cells and upon FOXM1 overexpression.
• Inhibition of autophagy (via ATG7, beclin-1 knockdown or chloroquine) partially restored docetaxel sensitivity in FOXM1-overexpressing cells.
• FOXM1 was found to target the AMPK/mTOR pathway to activate autophagy.

Conclusions:

• FOXM1 plays a critical role in mediating docetaxel resistance in CRPC.
• FOXM1 promotes docetaxel resistance by activating the autophagy pathway through the AMPK/mTOR signaling axis.
• Targeting FOXM1 and/or autophagy presents a promising therapeutic avenue for overcoming docetaxel resistance in CRPC patients.