β-Catenin overexpression is associated with gefitinib resistance in non-small cell lung cancer cells.
Pulmonary Pharmacology & Therapeutics(2014)
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 beta-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 beta-catenin in acquired resistance to EGFR-TKIs in NSCLC cell lines. Methods: The expression and transcriptional activity of beta-catenin were measured in both the NSCLC cell line PC9 and its sub-line PC9/AB(2) which has acquired resistance to gefitinib. Knockdown and overexpression of beta-catenin in the PC9/AB(2) 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 beta-catenin was increased in the PC9/AB(2) cells and the baseline expression of members of the beta-catenin signaling pathway was also higher in the PC9/AB(2) cells. Knocking down the expression of beta-catenin increased the sensitivity of the PC9/AB(2) cells to gefitinib by blocking the activation of the EGFR downstream pathways, while beta-catenin overexpression improved PC9 cells resistance to gefitinib by enhancing the activation of the EGFR and its downstream signaling. Conclusion: beta-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. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved.
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Key words
Non-small cell lung cancer,Epidermal growth factor receptor,Tyrosine kinase inhibitors,β-catenin,Gefitinib,Resistance
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