Inhibition of androgen receptor and β-catenin activity in prostate cancer

Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective approach to treating prostate cancer. Here we provide proof-of-concept that a small-molecule inhibitor of nuclear beta-catenin activity (called C3) can inhibit both the AR and beta-catenin-signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both beta-catenin/T-cell factor and beta-catenin/AR protein interaction, reflecting the fact that T-cell factor 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. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and beta-catenin cofactor, coactivator-associated arginine methyltransferase 1 (CARM1), providing 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 bicalutamide-resistant sphere-forming cells, indicating the therapeutic potential of this approach.