Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor
Journal
American Journal of Respiratory and Critical Care Medicine
Journal Volume
183
Journal Issue
8
Pages
1071-1079
Date Issued
2011
Author(s)
Chang T.-H.
Tsai M.-F.
Huang C.-P.
Yu Y.-L.
Lan C.-C.
Lin S.-B.
Wu C.-P.
Abstract
Rationale: 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. Objectives: 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 resistanceinvitro, and a xenograft mouse model was used forinvivo 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. Measurements and Main Results: 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. Conclusions: Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs.
SDGs
Other Subjects
BIM protein; caspase 9; gefitinib; messenger RNA; protein; transcription factor Slug; transcription factor Snail; transcription factor Twist; unclassified drug; zeb 1 protein; animal experiment; animal model; animal tissue; apoptosis; article; cancer cell; cell viability; controlled study; enzyme activation; epithelial mesenchymal transition; gene amplification; gene overexpression; gene silencing; human; human cell; IC 50; lung adenocarcinoma; male; mouse; nonhuman; pleura effusion; priority journal; protein expression; quantitative analysis; reverse transcription polymerase chain reaction; tumor growth; tumor xenograft; upregulation; Western blotting; Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Knockout Techniques; Humans; Lung Neoplasms; Mice; Neoplasms, Experimental; Quinazolines; Receptor, Epidermal Growth Factor; Transcription Factors
Type
journal article