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 interfering RNA-mediated specific reduction of COL11A1 protein levels increased the sensitivity of ovarian chemoresistant cells to cisplatin and paclitaxel. A combination of experimental approaches, including real-time RT-PCR, western blotting, luciferase assay and chromatin immunoprecipitation (ChIP) assays, showed that the c/EBPβ binding site on the COL11A1 promoter was identified as the major determinant of cisplatin and paclitaxel-dependent COL11A1 activation. Furthermore, COL11A1 silencing suppressed phosphorylated Akt expression, which was in concert with increased PDK1 degradation in chemoresistant cells. Analysis of 104 EOC patients showed that high COL11A1 mRNA levels are significantly associated with poor chemoresponse and poor clinical outcome. In conclusion, activation of COL11A1 by anticancer drugs confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPβ pathway and PDK1 stabilization. Note: This abstract was not presented at the meeting. Citation Format: Yi-Hui Wu. Chemoresistance regulation by COL11A1 in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4423. doi:10.1158/1538-7445.AM2015-4423
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