Abstract 583: Physiological concentrations of genistein reduced ER-α promoter methylation and increased ER-α expression in prostate cancer cells

Abstract

Abstract Prostate cancer is the most common malignancy and the second leading cause of cancer death among men in the United States. The lower incidence and mortality rates of prostate cancer in Asian population were correlated to the high dietary consumption of isoflavone-rich soy. One of the most abundant and potent isoflavones in soy is genistein which has an estradiol like structure and high affinity to estrogen receptor-α (ER-α). It has been suggested that genistein exerts its anti-cancer effects through binding to ER-α, the later has anti-proliferative and pro-apoptotic effects in prostate cancer. ER-α is mainly expressed in prostate epithelial cells and is downregulated in localized prostate cancer with increasing grade from Prostatic Intraepithelial Neoplasia (PIN) through low to high Gleason grade. This expression pattern supports the notion of a tumor suppressor role of ER-α. Therefore, ER-α agonists may be potential chemopreventive and therapeutic agents for prostate cancer. One of the mechanisms by which ER-α is suppressed in prostate cancer is promoter methylation, the extent of which correlates with the ER-α expression level which in turn may be linked to the degree of aggressiveness of prostate cancer. We examined the effects of physiological range of genistein concentrations (0.5, 1, and 10µM) on ER-α promoter methylation and ER-α expression in LNCaP, LAPC-4, and PC-3 prostate cancer cells that exhibit various basal levels of ER-α expression. We demonstrated for the first time that genistein caused a significant dose-dependent reduction in ER-α promoter methylation in LNCaP and LAPC-4 cells, using methylation specific PCR. There was a corresponding dose-related increase in ER-α mRNA and protein levels in these two cell lines assayed by quantitative RT-PCR and immunoblotting, respectively. However, ER-α expression levels and ER-α promoter methylation were not changed in PC-3 cells, which could be attributed to the low basal level of ER-α promoter methylation and the high basal level of ER-α expression in this cell line. These findings suggest that physiological concentrations of genistein is capable of reactivating tumor suppressor pathways by reversing ER-α promoter methylation with a subsequent restoration of the level of ER-α expression in prostate cancer cells that have higher basal levels of methylation. (Supported in part by Grant No. CA116195) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 583. doi:1538-7445.AM2012-583