Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/99313
標題: Cigarette smoke enhances oncogene addiction to c-MET and desensitizes EGFR-expressing non-small cell lung cancer to EGFR TKIs
作者: Tu, Chih-Yen
Cheng, Fang-Ju
Chen, Chuan-Mu
陳全木
Wang, Shu-Ling
Hsiao, Yu-Chun
Chen, Chia-Hung
Hsia, Te-Chun
He, Yu-Hao
Wang, Bo-Wei
Hsieh, I-Shan
Yeh, Yi-Lun
Tang, Chih-Hsin
Chen, Yun-Ju
Huang, Wei-Chien
關鍵字: EGFR-TKI
benzo[α]pyrene
c-MET
cigarette smoke
lung cancer
Benzo(a)pyrene
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
ErbB Receptors
HEK293 Cells
Humans
Models, Biological
Mutation
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-met
Smoking
Oncogenes
摘要: Cigarette smoking is one of the leading risks for lung cancer and is associated with the insensitivity of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, it remains undetermined whether and how cigarette smoke affects the therapeutic efficacy of EGFR TKIs. In this study, our data showed that chronic exposure to cigarette smoke extract (CSE) or tobacco smoke-derived carcinogen benzo[α]pyrene, B[α]P, but not nicotine-derived nitrosamine ketone (NNK), reduced the sensitivity of wild-type EGFR-expressing NSCLC cells to EGFR TKIs. Treatment with TKIs almost abolished EGFR tyrosine kinase activity but did not show an inhibitory effect on downstream Akt and ERK pathways in B[α]P-treated NSCLC cells. CSE and B[α]P transcriptionally upregulate c-MET and activate its downstream Akt pathway, which is not inhibited by EGFR TKIs. Silencing of c-MET reduces B[α]P-induced Akt activation. The CSE-treated NSCLC cells are sensitive to the c-MET inhibitor crizotinib. These findings suggest that cigarette smoke augments oncogene addiction to c-MET in NSCLC cells and that MET inhibitors may show clinical benefits for lung cancer patients with a smoking history.
URI: http://hdl.handle.net/11455/99313
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