Quercetin Inhibits AKT Ser473 Phosphorylation and Disrupts AKT-Androgen Receptor Signaling in Castration-Resistant...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Castration-resistant prostate cancer (CRPC) progression involves oxidative stress and the PI3K/AKT-androgen receptor (AR) axis.
• Quercetin (QRC), a dietary flavonol, has shown redox activity, but its precise role in CRPC is not fully understood.

Purpose of the Study:

• To investigate if Quercetin (QRC) suppresses androgen receptor (AR) output by directly modulating AKT in CRPC.
• To elucidate the mechanistic impact of QRC on the AKT-AR axis in CRPC.

Main Methods:

• CRPC cell lines (C4-2B, 22Rv1) were treated with varying QRC concentrations, with or without enzalutamide (Enz).
• Cell proliferation, viability, AKT and AR phosphorylation, AR abundance/localization, and PSA secretion were assessed.
• Molecular docking and dynamic simulations identified a potential QRC binding site on AKT.

Main Results:

• QRC exhibited dose-dependent cytostatic effects (IC50 ~21-24 μM) without significant cell death.
• QRC reduced AKT phosphorylation (pAKT S473) by up to 80% and decreased AR phosphorylation (pAR S210/213).
• QRC diminished nuclear AR and prostate-specific antigen (PSA) secretion; simulations indicated an allosteric binding site on AKT1.

Conclusions:

• Quercetin acts as an AKT-AR axis modulator in CRPC, potentially upstream of AR activation.
• These findings suggest QRC as a therapeutic agent for CRPC, offering a mechanism beyond simple oxidative stress scavenging.
• QRC's ability to target the AKT-AR axis provides a framework for novel CRPC treatment strategies.