Abstract #4508: Green tea polyphenol EGCG blunts nuclear shuttling of androgen receptor: novel insight into its androgen antagonistic function in prostate cancer

Data from cell culture, animal and clinical intervention studies strongly support the role of androgens in prostate cancer (CaP) growth, proliferation and progression. It is increasingly appreciated that androgen receptor (AR) mediates much of the biological actions of androgens. AR activity is considered critical for CaP progression and its transactivation is known to enhance CaP cell survival. Oral consumption of green tea polyphenols containing epigallocatechin-3-gallate (EGCG) to TRAMP and other mouse models and in some settings to human CaP patients affords substantial CaP chemopreventive effects. Understanding the mechanism of these biological effects of EGCG is critical for its possible development as an agent for the management of CaP. Here we provide evidence that these effects, at least in part, are due to the androgen antagonistic nature of EGCG. EGCG was found to compete with high affinity, labeled AR agonist, Alarmone, to interact with the ligand binding domain of AR with an IC₅₀ of 0.4 µM. By binding to AR, EGCG at the dose as little as 10 µM was found to inhibit the interdomain interaction (N-C terminus interaction) required for maximal AR activation. As a consequence, treatment with EGCG dose-dependently repressed the transcriptional activation by a hotspot mutant AR (AR877) expressed ectopically in CV1 receptor negative cells as well as the endogenous AR mutant in LNCaP cells. To test whether EGCG inhibits nuclear shuttling of AR to nucleus, xenografts of CaP 22Rv1 cells were established in athymic male nude mice and they were treated with EGCG (1 mg per mice thrice weekly). Six weeks later excised tumors were analyzed to detect AR protein expression by performing immunohistochemistry. EGCG treatment was found to inhibit nuclear shuttling of mutant AR and significantly repressed AR expression. Since the growth of CaP cells is regulated by functional AR mediated signaling and since AR transactivation is known to positively stimulate growth of CaP cells, we hypothesized that by blunting AR function EGCG will repress CaP growth. We determined the effect of EGCG on the growth of hormone R1881 stimulated CaP LNCaP cells employing MTT assay. R1881 treatment accelerated cell growth however co treatment with EGCG significantly repressed the growth. Taken together, we provide evidence that EGCG functionally antagonizes with androgens resulting in AR repression at multiple levels leading to repression of CaP growth. We therefore suggest that EGCG could be developed to treat locally advanced human CaP.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4508.