Cotinine Enhances Androgen Receptor Stability and Promotes Androgen-Dependent Proliferation in Prostate Cancer Cells:...

Cigarette smoking is associated with a poor prognosis and reduced efficacy of androgen receptor signaling inhibitors (ARSIs) in prostate cancer patients; however, the underlying molecular mechanisms remain largely undefined. This study investigated the impact of cotinine, the stable primary metabolite of nicotine, on androgen-dependent growth and therapeutic sensitivity in human prostate cancer 22Rv1 cells. While cotinine alone did not affect basal prostate-specific antigen (PSA) levels, it significantly potentiated 5α-androstane-3,17-dione (5α-Adione)-induced PSA expression and cell proliferation. Mechanistic investigations revealed that cotinine did not modulate the expression levels of androgen-synthesizing enzymes (e.g., AKR1C3, DHRS11) and E3 ubiquitin ligases. Instead, cotinine significantly extended the protein half-life of both the full-length androgen receptor (AR) and the constitutively active splice variant AR-V7. Co-immunoprecipitation assays indicated that cotinine increased the association between AR and the molecular chaperone HSP70, thereby protecting AR proteins from ubiquitin-proteasome-mediated degradation. Collectively, these findings provide a molecular basis for the adverse clinical outcomes observed in smokers, suggesting that the accumulation of cotinine may serve as a potential risk factor for prostate cancer progression and treatment resistance.