| Androgen receptor (AR) is the major therapeutic target in prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could be an effective approach to treating prostate cancer. This study provided evidence that the Wnt/beta-catenin pathway can be activated in prostate cancer cells after androgen-deprivation therapy and thereby promote androgen-independent growth, partly through enhanced interaction of beta-catenin with TCF4. Inhibition of the Wnt/beta-catenin pathway increased sensitivity of prostate cancer cells to antiandrogen. Further, combined treatment of antiandrogen and Wnt/beta-catenin inhibitor caused synergistic repression of prostate cancer cell growth.;This study also provided proof-of-concept that a small molecule inhibitor of nuclear beta-catenin activity (called C3) can inhibit both the AR and Wnt/beta-catenin pathways in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both beta-catenin/TCF and beta-catenin/AR protein interaction, reflecting the fact that TCF and AR have overlapping binding sites on beta-catenin. Given that AR interacts with, and is transcriptionally regulated by beta-catenin, C3 treatment also resulted in decreased occupancy of beta-catenin on the AR promoter and diminished AR and AR/beta-catenin target gene expression. Surprisingly, C3 treatment resulted in decreased nuclear localization of AR and AR binding to target genes, providing new insight into the unrecognized function of beta-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model, and blocked renewal of the sphere forming cells that are resistant to conventional antiandrogen, indicating its promising therapeutic potential. |
