Slug Confers Resistance to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

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Title:	Slug Confers Resistance to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor
Authors:	余永倫;Yu, Yung-luen;Yang CH,;Lin SB,;Wu, CP;Shih, JY;Yang, PC
Contributors:	生物科技學系
Keywords:	Slug;geﬁtinib resistance;apoptosis;epithelial mesenchymal transition
Date:	2011-04
Issue Date:	2012-11-23 09:15:07 (UTC+0)
Abstract:	"Non-small cell lung cancers carrying epidermal growth factor receptor (EGFR) mutations respond well to EGFR tyrosine kinase inhibitors (TKIs), but patients ultimately develop drug resistance and relapse. Although epithelial-mesenchymal transition (EMT) can predict resistance to EGFR TKIs, the molecular mechanisms are still unknown. To examine the role of EMT regulators in resistance to gefitinib. Methods: The expression level of EMT regulators in gefitinib-sensitive cells (PC9) and gefitinib-resistant cells (PC9/gef) was determined using quantitative real-time reverse transcription-polymerase chain reaction and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of EMT regulators on gefitinib resistance in vitro, and a xenograft mouse model was used for in vivo confirmation. In addition, cancer cells from 44 patients with malignant pleural effusions of lung adenocarcinoma were collected for analysis of EMT regulator mRNA by quantitative real-time reverse transcription-polymerase chain reaction. Slug expression, but not that of snail, twist, or zeb-1, was significantly increased in PC9/gef compared with PC9 cells. Slug knockdown in PC9/gef cells reversed resistance to gefitinib, and overexpression of Slug in PC9 cells protected cells from gefitinib-induced apoptosis. Silencing of Slug in gefitinib-resistant cells restored gefitinib-induced apoptosis primarily through Bim up-regulation and activation of caspase-9. Slug enhanced tumor growth in a xenograft mouse model, even with gefitinib treatment. In clinical samples, Slug expression was significantly higher in cancer cells with resistance to EGFR TKIs than in treatment-naive cancer cells. Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs."
Relation:	AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Appears in Collections:	[Department of Biotechnology] Journal Article

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