Abstract 192: Restoration of an epigenetically silenced tumor suppressor gene RASSF1A in human prostate cancer cells by a plant alkaloid, mahanine

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The etiology of human prostatic carcinoma remains largely undefined. However, it is becoming clear that epigenetic inactivation of various tumor suppressor genes could play pivotal role in the development of various cancers including prostate cancer. One of such tumor suppressor is Ras-association domain family 1 (RASSF1) gene. Epigenetic inactivation of RASSF1A is probably the most frequently methylated gene described thus far in human cancer. Ectopic expression of RASSF1A in cancer cells that lack endogenous RASSF1A transcripts resulted in reduced growth of cancer cells in vitro and in nude mice supporting a role for RASSF1A as a tumor suppressor gene. Since, the restoration of RASSF1A expression in tumor cells impairs their tumorigenicity, factors that restore RASSF1A expression have immense importance in preventing tumor growth. In this investigation, we demonstrated that, mahanine, a plant derived carbazole alkaloid, restores RASSF1A expression in both androgen-responsive (LNCaP) and androgen-negative (PC3) prostate cancer cells by inhibiting DNA methyltransferase (DNMT) activity. Mahanine-induced expression of RASSF1A in turn significantly reduces cyclin D1 but not other cyclins. As a result of down-regulation of cyclin D1, cancer cells arrest at G0/G1 phase. To understand the inverse relationship between RASSF1A and cyclin D1, we observed that mahanine treatment down-regulates cyclin D1 and addition of RASSF1A siRNA prevents this inhibition. Inactivation of both Akt and CREB by mahanine and RASSF1A is associated with the down-regulation and translocation of cyclin D1. This study shows that mahanine can reverse an epigenetically silenced gene, RASSF1A in prostate cancer cells by inhibiting DNMT activity that in turn down-regulates a key cell cycle regulator, cyclin D1. Mahanine, therefore, promises an encouraging therapeutic choice for advanced prostatic cancer (Supported by NIH grant R01 CA131123). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 192.