Abstract
Abstract FoxM1 is a member of Forkhead transcription factors and its expression has been found to be altered in a variety of cancers. Several studies have indicated the importance of FoxM1 in cell proliferation, as it is a key cell-cycle regulator of both the transition from G1 to S phase and the progression to mitosis. In this study, we investigated the functional consequences of FoxM1 signaling pathway in a large cohort of epithelial ovarian cancer (EOC) tumor (patient) samples, panel of cell lines, and in nude mouse model. Using immunohistochemistry, FoxM1 was detected in 47.4% (64/135) of the ovarian tumor samples. EOC with FOX-M1 expression showed a significantly better disease free survival(p=0.0148) of 21.9 months as compared to the EOC with low FOX-M1 expression(14.4 months). Overexpression of FoxM1 was also significantly associated with activated p-AKT(p=0.0072), SKP2(p=0.0121), p-Rb(p=0.0357), UBE2C(p=0.0106), FAS-N(p=0.0179), PIK3CA p110αIHC(p=0.0362), XIAP(p=0.0033) and tumor proliferative marker Ki167 (p<0.0001). Treatment of a panel of EOC cell lines with thiostrepton, an inhibitor of FoxM1, inhibited cell proliferation and induced apoptosis. Thiostrepton treatment caused apoptosis by involving the mitochondrial pathway, through activation of caspases and down regulation of XIAP and survivin. FoxM1 inhibition in EOC cells by thiostrepton resulted in the down regulation of Skp2 and accumulation of p21, possibly causing G2/M arrest. Furthermore, FoxM1 inhibition also down regulated cell migration and cell invasion in EOC cells by inducing decreased secretion of VEGF and MMP2. In addition, pharmacological inhibition of FoxM1 or its gene silencing with siRNA causes downregulation of FoxM1, AKT and its associated downstream signaling molecules. Altogether, these results suggest that FoxM1 and its role in the deregulated survival pathway make this a potential target for therapeutic intervention of EOC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1008. doi:10.1158/1538-7445.AM2011-1008
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