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

• Published in: Biochemical and biophysical research communications Vol. 468; no. 1-2; pp. 173 - 178
• Main Authors: Barghout, Samir H., Zepeda, Nubia, Xu, Zhihua, Steed, Helen, Lee, Cheng-Han, Fu, YangXin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.12.2015
• Subjects: 60 APPLIED LIFE SCIENCES; Antineoplastic Agents - pharmacology; Base Sequence; beta Catenin - antagonists & inhibitors; beta Catenin - genetics; beta Catenin - metabolism; Carboplatin; Carboplatin - pharmacology; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Chemoresistance; CHEMOTHERAPY; DIAGNOSIS; Drug Resistance, Neoplasm - drug effects; Epithelial ovarian cancer; Exons; Female; GENES; Humans; INHIBITION; LIGANDS; MORTALITY; NEOPLASMS; Neoplasms, Glandular and Epithelial - drug therapy; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; OVARIES; Ovary - drug effects; Ovary - metabolism; PATIENTS; TOXICITY; Transcriptional Activation - drug effects; Up-Regulation - drug effects; Wnt Signaling Pathway - drug effects; Wnt/β-catenin; WOMEN; Carboplatin; Epithelial ovarian cancer; Wnt/β-catenin; Chemoresistance
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.10.138

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/β-catenin signaling components in the paired cisplatin-sensitive (A2780s) 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/β-catenin target genes are upregulated in A2780cp cells compared to A2780s cells, suggesting that Wnt/β-catenin signaling is more active in A2780cp cells. Further analysis revealed nuclear localization of β-catenin and higher β-catenin transcriptional activity in A2780cp cells compared to A2780s cells. Finally, we demonstrated that chemical inhibition of β-catenin transcriptional activity by its inhibitor CCT036477 sensitized A2780cp cells to carboplatin, supporting a role for β-catenin in carboplatin resistance in A2780cp cells. In conclusion, our data suggest that increased Wnt/β-catenin signaling activity contributes to carboplatin resistance in A2780cp cells. •Wnt ligands and target genes are upregulated in cisplatin resistant A2780cp cells.•Negative regulators of Wnt signaling are down-regulated in A2780cp cells.•β-catenin transcriptional activity is higher in A2780cp cells compared to A2780s cells.•Inhibition of β-catenin activity increases carboplatin cytotoxicity in A2780cp cells.