Abstract 3795: STAT-3: A Novel Target of Diindolylmethane in Ovarian Cancer

Abstract

Abstract Signal transducers and activation of transcription (STATs) are the important for growth and development. However defects in STAT's may lead to malignant transformation. STAT-3 is an oncogene which is over expressed in several cancers including ovarian cancer. We have previously demonstrated that Diindolylmethane (DIM), an active metabolite of Indole-3-Carbinol present in cruciferous vegetables, is effective in suppressing the proliferation of human ovarian cancer cells, however, the mechanism through which DIM reduces the growth of cancer cells was not clear. We hypothesized that DIM inhibits the growth of ovarian cancer cells by inhibiting STAT-3 activation. Our present studies demonstrate that DIM treatment inhibit the phosphorylation of STAT-3 at Tyr-705 and Ser-727 in a concentration-dependent manner in SKOV-3 and OVCAR-3 cells. Interestingly, DIM treatment also reduced the constitutive protein expression of STAT-3 in both the cell lines. In a time dependent study, we observed that STAT-3 inhibition was as early as 1h after DIM treatment. Next, we wanted to see whether DIM can block IL-6 mediated activation of STAT-3. Treatment of SKOV-3 or OVCAR-3 cells with 5ng/ml IL-6 for 15min increase the activation of STAT-3 by phosphorylation at Tyr705 by almost twenty fold. Our results reveal that DIM treatment almost completely blocked IL-6 induced phosphorylation of STAT-3 at Tyr705 in both SKOV-3 and OVCAR-3 cells and completely in TOV-21G cells. STAT-3 after activation translocate to nucleus, bind to DNA and is involved in the transcription of responsive genes such as Mcl-1, survivin and Bcl-2. Our results demonstrate that DIM inhibits the DNA binding activity of STAT-3 resulting in the reduced expression of Mcl-1, survivin and Bcl-2. Overexpression of STAT-3 by gene transfection abrogates the cell growth inhibitory effects of DIM. Taken together, our cellular results establish STAT-3 as a therapeutic target of DIM in ovarian cancer. Furthermore, our just completed in vivo studies indicate that oral administration of 2mg DIM per day for 6 weeks significantly suppressed the growth of SKOV-3 tumor xenografts in athymic nude mice. Whether SKOV-3 ovarian tumor growth suppression is through inhibition of STAT-3 in vivo is currently under investigation. [Supported in part by RO1 CA 106953 and CA 129038 awarded to S.K.S by NIH] 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 3795.