Elevated β-catenin activity contributes to carboplatin resistance in A2780cp ovarian cancer cells

Ovarian cancer is the fifth leading cause of cancer-related mortalities in women. Epithelial ovarian cancer (EOC) represents approximately 90% of all ovarian malignancies. Most EOC patients are diagnosed at advanced stages and current chemotherapy regimens are ineffective against advanced EOC due to the development of chemoresistance. It is important to better understand the molecular mechanisms underlying acquired resistance to effectively manage this disease. In this study, we examined the expression of the Wnt/beta-catenin signaling components in the paired cisplatin-sensitive (A27805) and cisplatin-resistant (A2780cp) EOC cell lines. Our results showed that several negative regulators of Wnt signaling are downregulated, whereas a few Wnt ligands and known Wnt/beta-catenin target genes are upregulated in A2780cp cells compared to A2780s cells, suggesting that Wnt/beta-catenin signaling is more active in A2780cp cells. Further analysis revealed nuclear localization of beta-catenin and higher beta-catenin transcriptional activity in A2780cp cells compared to A2780s cells. Finally, we demonstrated that chemical inhibition of beta-catenin transcriptional activity by its inhibitor CCT036477 sensitized A2780cp cells to carboplatin, supporting a role for beta-catenin in carboplatin resistance in A2780cp cells. In conclusion, our data suggest that increased Wnt/beta-catenin signaling activity contributes to carboplatin resistance in A2780cp cells. (C) 2015 Elsevier Inc. All rights reserved.