Prostate cancer (PCA) is the second leading cause of cancer-related deaths in men in western society. The long latency involved in the development of clinically significant disease provides plethora of opportunities for its management especially using prevention approaches. 2-Methoxyestradiol (2-ME), an endogenous metabolite of 17-ß estradiol, has shown promising anti-proliferative efficacy against various cancer cells including prostate. Reports from our laboratory showed that 2-ME (i) inhibits proliferation of both androgen responsive and independent cells through induction of apoptosis involving G2/M checkpoint block, and (ii) prevents the development of prostate tumors in transgenic adenocarcinoma of mouse prostate (TRAMP) model. Although various mechanisms have been proposed, the precise molecular mechanisminvolved in its anti-proliferative activity is still uncertain. Our studies show that 2-ME induces apoptosis in prostate cancer cells through down regulation of FLIP (FADD-Like interleukin-1β-converting enzyme (FLICE) inhibitory protein), a key regulator of apoptosis. 2-ME reduced the expression of FLIP message indicating a role for transcriptional regulation. Transient transfection assays using full-length FLIP promoter (-1293/+242) showed higher constitutive levels of FLIP promoter activity in androgen independent prostate cancer cells which was inhibited with 2-ME. Overexpression of either super-repressor of NFκB or kinase dead mutant of Akt inhibited FLIP promoter activity. Immunoprecipitation experiments showed decreased formation of DISC that is accelerated with 2-ME treatment. These results may provide a molecular basis for the ability of 2-ME to suppress proliferation and to induce apoptosis. Supported by RSG-04-169 from American Cancer Society (APK).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA