Abstract 1823: Mechanism of the anterograde transport of the androgen receptor

Abstract Androgen receptor (AR) is a ligand-activated nuclear receptor that plays a critical role in normal prostate physiology, as well as in the development and progression of prostate cancer. In addition to the classical paradigm in which AR exerts its biological effects by activating the transcription of its target genes, there is considerable evidence to support a rapid, non-genomic action mediated by membrane-associated AR, which facilitates the activation of kinase signaling cascades, leading to cell proliferation. While the nuclear translocation of AR is well studied, the molecular events controlling the recruitment of AR to the plasma membrane remain poorly understood. In this study, we set out to elucidate the mechanism underlying AR transport to the membrane. We found that a subpopulation of AR was localized to the membrane fraction shortly after androgen stimulation. Treatment with microtubule-targeting agents, but not actin inhibitors, blocked androgen-induced AR membrane localization, suggesting that AR transport to the membrane is mediated by the microtubule cytoskeleton. By utilizing dominant negative mutants, we identified the KIF5B, a member of the kinesin 1 family of motor proteins, is involved in the anterograde transport of AR. We further demonstrated that AR interacts directly with KIF5B, and such interaction is enhanced by androgens. Through a series of deletion constructs, a region includes the N-terminal and DNA binding domains of AR was determined to be involved in the association with KIF5B. Disruption of AR membrane transport decreased AKT phosphorylation. Together, our data suggest that KIF5B mediates AR membrane transport and regulates the non-genomic function of AR. Disruption of AR membrane translocation may represent a novel strategy to target AR signaling in prostate cancer. Citation Format: Jianzhuo Li, Guanyi Zhang, Hee-Won Park, Haitao Zhang. Mechanism of the anterograde transport of the androgen receptor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1823.