Stilbenes Inhibit Androgen Receptor Expression in 22Rv1 Castrate-resistant Prostate Cancer Cells

Abstract

Androgen receptor (AR) signaling plays an important role in the development and progression of prostate cancer (PCa). Importantly, AR continues to be expressed in advanced stages of castrate-resistant PCa (CRPC), where it can have ligand- independent activity. Identification of naturally occurring substances which can inhibit AR expression holds promise for PCa chemoprevention and therapy. We have previously shown that resveratrol (Res) inhibits androgen-promoted growth, AR expression and transactivation in androgen-responsive non-metastatic LNCaP PCa cells. In the current study, we investigated the effects of Res and its three natural analogs: trimethoxy-resveratrol (3M-Res), pterostilbene (Pter) and piceatannol (Pic) on growth of 22Rv1 castrate-resistant cells, which express wild type (AR114/110) and truncated form (AR80) of AR. We found that although all the stilbenes inhibited the proliferation of 22Rv1 cells in a dose-dependent manner, 3M-Res was the most potent inhibitor. We also found that while AR114/110 responded to the synthetic androgen agonist methyltrienolone (R1881) as well as to antiandrogen Flutamide AR80, which lacks ligand-binding domain, did not respond to R1881 but was inhibited by Flutamide. Interestingly, Res, Pter and Pic but not 3M-Res, like Flutamide, inhibited both AR114/110 and AR80, with the effect on AR80 being more prominent when high concentrations of the stilbenes were used. Taken together, these data indicate both AR-independent (3M-Res) and possible AR-dependent (Res, Pter, Pic) mechanisms of cell growth inhibition by these stilbenes. These findings provide evidence for the potential use of these stilbenes in arresting the progression of CRPC.