Abstract 958: Activation of COL11A1 by anticancer drugs through IGF-1R/PI3K pathway confers chemoresistance in ovarian cancer via activating NF-κB-mediated Twist1 expression

Abstract

Abstract Epithelial ovarian carcinoma remains the most lethal gynecologic malignancy. While initial response to first-line therapy (consisting of surgical cytoreduction and combination platinum/taxane therapy) is usually effective, the majority of patients will ultimately recur with chemotherapy-resistant cancer and succumb to disease. Biomarkers that predict patient's responsiveness to chemotherapy might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the molecular mechanisms of collagen type XI alpha 1 (COL11A1) in chemo-resistance of ovarian cancer. We analyzed the expression profiles of 60 epithelial ovarian cancer tissue samples obtained at first cytoreductive surgery to identify genes linked with chemotherapy response. Among the 47 selected genes, collagen type XI alpha 1 (COL11A1) was the most highly elevated in chemo-resistance tumors. Small interference RNA-mediated specific reduction in COL11A1 protein levels increased the sensitivity to cisplatin and taxol in ovarian cancer cells. A combination of experimental approaches, including real-time RT-PCR, western blotting, luciferase assay and chromatin immunoprecipitation (ChIP) assays, showed that COL11A1 knockdown attenuated Twist1 expression and suppressed binding of NF-κB to its putative Twist1 promoter binding site, suggesting that the NF-κB/Twist1 axis is upregulated by COL11A1. Cisplatin and taxol treatment triggers the activation of IGF-1R/PI3K signaling cascades, leading to activation of COL11A1 and Twist1. Pharmacological inhibition of PI3K abrogated the cisplatin and taxol-triggered, COL11A1-dependent chemo-resistance. Furthermore, the c/EBPβ binding site on the COL11A1 promoter was identified as the major determinant of cisplatin and taxol-dependent COL11A1 activation. Analysis of 88 ovarian cancer patients indicated that high COL11A1 mRNA levels are significantly associated with high Twist1 mRNA levels and poor clinical outcome. We conclude that activation of COL11A1 by anti-cancer drugs through IGF-1R/PI3K pathway confers chemo-resistance in ovarian cancer cells via activating NF-κB-mediated Twist1 expression. Citation Format: Yi-Hui Wu, Yu-Fang Huang, Cheng-Yang Chou. Activation of COL11A1 by anticancer drugs through IGF-1R/PI3K pathway confers chemoresistance in ovarian cancer via activating NF-κB-mediated Twist1 expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 958. doi:10.1158/1538-7445.AM2014-958