Abstract POSTER-THER-1409: Targeting p53-FoxM1 axis in ovarian cancer

Abstracts: 10th Biennial Ovarian Cancer Research Symposium; September 8-9, 2014; Seattle, WAFoxM1, a member of the Forkhead transfection factors, has been found to be overexpressed in many human cancers including ovarian cancer. Although FoxM1 is known to be downregulated by p53, the molecular mechanisms are not well characterized. In this study, we used the MDM2 inhibitor Nutlin-3 as a tool to modulate p53 expression and investigated the mechanism by which p53 regulates FoxM1 expression in ovarian cancer cells. We observed that Nutlin-3 upregulated p53 protein and downregulated FoxM1 mRNA and protein levels in ovarian cancer cell lines with wild type TP53 , but not in cell lines with mutant TP53 . This effect was at least partially blocked by cycloheximide or actinomycin D, indicating a transcription- and translation-dependent mechanism. Pulse-chase studies revealed that downregulation of FoxM1 by Nutlin-3 is due to enhanced FoxM1 mRNA decay. Knockdown of p53 using shRNAs abrogated the suppression of FoxM1 expression by Nutlin-3, indicating a p53-dependent mechanism. Furthermore, silencing of FoxM1 by shRNAs in ovarian cancer cells with or without wild-type TP53 led to a significant decrease in cell proliferation. The FoxM1 inhibitor, thiostrepton, induces cytotoxicity in ovarian cancer cell lines and enhances sensitivity to cisplatin in these cells. Thiostrepton downregulates FoxM1 expression in several ovarian cancer cell lines and enhances sensitivity to carboplatin in vivo. Finally, FoxM1 expression is elevated in nearly all (47/48) ovarian tumors. In summary, the present study provides novel evidence that p53 downregulates FoxM1 in ovarian cancer cells at least in part by destabilizing FoxM1 mRNA and that FoxM1 may be targeted for therapeutic benefits in ovarian cancer.Citation Format: Xuan Zhang, Lihua Cheng, Kay Minn, Magdalena Waggoner, Nikhil K. Parelkar, Iman Jokar, George A. Vielhauer, Rashna Madan, Andrew K. Godwin, Viji Shridhar,, Jeremy Chien. Targeting p53-FoxM1 axis in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1409.