Abstract
Prostate cancer that recurs following androgen-deprivation therapy is termed castration-resistant, which is incurable and is marked by reactivation of androgen receptor (AR) signaling. KIF20A, a kinesin with unique structural features, is overexpressed in human castration-resistant prostate cancer (CRPC) compared to androgen-dependent PC and benign tissue. KIF20A has well-described roles in mitotic processes, but it has a less characterized function in vesicle fission and trafficking within Golgi-driven secretory pathways. Stable expression of KIF20A in androgen-dependent PC cells promoted progression to CRPC through the activation of AR signaling in vitro and in vivo. KIF20A expression resulted in the secretion of autocrine factors in the conditioned media that activated AR and caused castration-resistant proliferation of naïve androgen-dependent cells. KIF20A-driven castration-resistant growth depends on vesicle biogenesis (using GW4869), and isolated vesicles from KIF20A cells retained the ability to confer castration-resistant proliferation in androgen-dependent cells. KIF20A depletion or treatment with the KIF20A-specific inhibitor, paprotrain, reduced CRPC and enzalutamide (AR antagonist)-resistant CRPC cell growth. These data are the first to establish KIF20A as a driver of CRPC progression through autocrine AR activation and implicate KIF20A as a promising therapeutic target against CRPC.