Coregulation of srGAP1 by Wnt and Androgen Receptor Signaling: A New Target for Treatment of CRPC

Abstract

Abstract : Androgen receptor (AR) and Wnt signaling both play a critical role during prostate cancer progression to castration-resistance prostate cancer (CRPC). Over expression of AR can activate transcriptional activities of Wnt signaling pathway and promote CRPC. Recent data in our laboratory showed a potential co-regulation of srGAP1 (Slit-Robo-GTPase activating protein1) and active Wnt and AR signaling in CRPC. srGAP1 is a downstream component of Slit-Robo signaling. Our data showed that srGAP1 is overexpressed in CRPC cell lines (androgen-insensitive prostate cancer) while absent in both androgen-sensitive cells and in normal prostate epithelial cells. We also detected increased srGAP1 and LEF-1 expression in human CRPC tissues compared with normal epithelial prostate and androgen sensitive prostate cancer tissues by immunohistochemistry analysis. When androgen-sensitive LNCaP cells were grown under androgen deprived condition, we observed induced expression of srGAP1. Interestingly, srGAP1 expression was also increased when LNCaP cells were grown under Wnt stimulated conditions. And, srGAP1 expression was decreased when Wnt signaling was inhibited by a Wnt antagonist Wnt-inhibitory factor-1 (WIF-1) in CRPC cell lines. Chromatin immmunoprecipitation assay was performed to examine whether Wnt transcription factor TCF-4 binds to the srGAP1 promoter. Overexpression of WIF-1 inhibited the promoter activity of srGAP1. Taken together, our results indicated that srGAP1 is co-regulated by both Wnt and AR signaling and srGAP1 may be a new potential Wnt target gene in castration-resistance prostate cancer.