Mig-6 overcomes gefitinib resistance by inhibiting EGFR/ERK pathway in non-small cell lung cancer cell lines.
Non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and is the most common cause of lung cancer death. Currently, the epidermal growth factor receptor inhibitor gefitinib is widely used for patients with advanced NSCLC. However, drug resistance is a major obstacle. Mig-6 is a feedback inhibitor of EGFR and its down-stream pathway; it has been shown to play a role in gefitinib sensitivity. There is neither systematical research on the relationship between Mig-6 expression and gefitinib sensitivity, nor has the contribution of up-regulated Mig-6 on the gefitinib-resistant cell lines. In the present work, four NSCLC cell lines (H1299, A549, PC-9, and PC-9/AB11) with different sensitivities to gefitinib were subjected to analysis of the expression of Mig-6. We found that Mig-6 is over-expressed in gefitinib-sensitive NSCLC cell lines, but is low in gefitinib-resistant NSCLC cell lines. Further analysis revealed that over-expression of Mig-6 increased cell apoptosis and inhibited proliferation of gefitinib-resistant NSCLC cells treated with gefitinib, whereas lowering the expression of Mig-6 decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in gefitinib-sensitive NSCLC cell lines. These results suggest that Mig-6 is involved in mediating the response to gefitinib in NSCLC cell lines. Additionally we demonstrated that Mig-6 could reverse gefitinib resistance through inhibition of EGFR/ERK pathway in NSCLC cells. Our work uncovered that Mig-6 may be an effective therapeutic target in gefitinib-resistant lung cancer patients.
Department of Radiology and Key Laboratory of Diagnostic Imaging and Interventional Radiology, The First Affiliated Hospital of China Medical University Shenyang 110001, P. R. China ; Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical University Shenyang 110001, P. R. China.
Zi-Xuan
ZX
Li
Department of Pharmacy, The First Affiliated Hospital of China Medical University Shenyang 110001, P. R. China.
Lian-Yue
LY
Qu
Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical University Shenyang 110001, P. R. China ; Shiyan Taihe Hospital Shiyan 442000, P. R. China.
Hi
H
Wen
Department of Radiology and Key Laboratory of Diagnostic Imaging and Interventional Radiology, The First Affiliated Hospital of China Medical University Shenyang 110001, P. R. China.
Hong-Shan
HS
Zhong
Department of Radiology and Key Laboratory of Diagnostic Imaging and Interventional Radiology, The First Affiliated Hospital of China Medical University Shenyang 110001, P. R. China.
Ke
K
Xu
Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical University Shenyang 110001, P. R. China.
Xue-Shan
XS
Qiu
Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical University Shenyang 110001, P. R. China.
En-Hua
EH
Wang
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D025521:Tumor Suppressor Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib
EGFR signaling; Mig-6; NSCLC; gefitinib resistance