β-Catenin overexpression is associated with gefitinib resistance in non-small cell lung cancer cells

• Published in: Pulmonary pharmacology & therapeutics 2014-06, Vol.28 (1), p.41-48
• Main Authors: Fang, Xia, Gu, Pan, Zhou, Caicun, Liang, Aibin, Ren, Shenxiang, Liu, Fang, Zeng, Yu, Wu, Yunjin, Zhao, Yinmin, Huang, Binbin, Zhang, Zongmei, Yi, Xianghua
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; beta Catenin - genetics; beta Catenin - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Survival - drug effects; Drug Resistance, Neoplasm; Epidermal growth factor receptor; Gefitinib; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical Education; Non-small cell lung cancer; Pulmonary/Respiratory; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Resistance; Signal Transduction - drug effects; Tyrosine kinase inhibitors; β-catenin
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2013.05.005

Abstract Background Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) presents great challenges in the treatment of non-small cell lung cancer (NSCLC) patients, while the mechanisms are still not well understood. The β-catenin signaling pathway has been found to be associated with chemoresistance and can activate the EGFR and its downstream pathways. This study aimed to investigate the role of β-catenin in acquired resistance to EGFR-TKIs in NSCLC cell lines. Methods The expression and transcriptional activity of β-catenin were measured in both the NSCLC cell line PC9 and its sub-line PC9/AB2 which has acquired resistance to gefitinib. Knockdown and overexpression of β-catenin in the PC9/AB2 and PC9 cells were performed. The cell survival rate and the activation of the EGFR and its downstream pathways were detected in the two cell lines after transfection. Results Nuclear translocation of β-catenin was increased in the PC9/AB2 cells and the baseline expression of members of the β-catenin signaling pathway was also higher in the PC9/AB2 cells. Knocking down the expression of β-catenin increased the sensitivity of the PC9/AB2 cells to gefitinib by blocking the activation of the EGFR downstream pathways, while β-catenin overexpression improved PC9 cells resistance to gefitinib by enhancing the activation of the EGFR and its downstream signaling. Conclusion β-catenin plays an important role in acquired resistance to EGFR-TKIs in NSCLC cell lines and may be a potential therapeutic target for NSCLC patients who have failed to respond to targeted therapy.