Abstract
BACKGROUND AND OBJECTIVE: It has been known that hepatocyte growth factor (HGF) induces gefitinib resistance in non-small cell lung cancer (NSCLC) cells. The possible mechanism may be related to the activation of the HGF receptor c-Met. The aim of this study is to investigate the involvement of c-Met and its downstream signaling pathway in the HGF-induced gefitinib resistance of NSCLC cells with different epidermal growth factor receptor (EGFR) gene types. METHODS: NSCLC cell lines with different EGFR genes (PC-9, PC9/R, H292, and A549) were selected and induced by HGF. Cell survival was determined by MTT assay and the expression of Met and downstream signaling proteins were examined by Western blot. RESULTS: Gefitinib inhibited the cell growth of PC9, H292, and A549 cell lines in a dose-dependent manner. The concentration-survival curve notably shifted to the right when induced by HGF. The apoptotic rate was lower when the cells were treated with HGF and gefitinib than when these cells were treated with gefitinib alone (P<0.05), particularly in PC9, H292, and A549 cells, but not in PC9/R. HGF stimulated the phosphorylation of Met and downstream signaling proteins in PC9, H292, PC9/R, and A549 cell lines. p-Met, p-Akt, p-Stat3, and p-Erk1/2 expressions were higher when the cells were treated with HGF and gefitinib than when these cells were treated with gefitinib alone, particularly in PC9, H292, and A549 cells, but not in PC9/R. CONCLUSIONS: c-Met and its downstream signaling pathway possibly participated in the HGF-induced gefitinib resistance in NSCLC cells with different EGFR gene types.