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HGF Increases Cisplatin Resistance via Down-Regulation of AIF in Lung Cancer Cells

¹ Feng-Yuan Hospital, Feng-Yuan; ² Graduate Institute of Veterinary Microbiology, and ⁴ Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung; ³ Department of Dental Laboratory Technology, Central Taiwan University of Science and Technology, Taichung; and ⁵ Comprehensive Cancer Center, China Medical University Hospital, Taichung, Taiwan

Correspondence and requests for reprints should be addressed to Kuan-Chih Chow, PhD, Graduate Institute of Biomedical Sciences, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung, 40227 Taiwan. E-mail: kcchow{at}dragon.nchu.edu.tw

Our previous study had shown that advanced stages of lung adenocarcinomas (ADC) was frequently associated with overexpression of hepatocyte growth factor (HGF), which has multipotent and anti-apoptotic activities. In this study, we examined the effect of HGF on gene expression of apoptosis-inducing factor (AIF) and cisplatin sensitivity in lung ADC cells. Expression of AIF was determined by immunocytochemistry and confocal immunofluorescence microscopy. Our data show that addition of HGF suppressed AIF expression and increased cisplatin resistance. The effect could be through HGF receptor and its downstream effector, focal adhesion kinase (FAK). Interestingly, knockout of FAK gene increased AIF expression and drug sensitivity. Re-introduction of FAK gene, on the other hand, restored drug resistance. These results suggested that HGF might induce cisplatin resistance via c-Met to activate FAK and down-regulate AIF expression.

Key Words: apoptosis inducing factor • cisplatin resistance • hepatocyte growth factor • focal adhesion kinase • non–small cell lung cancer

CLINICAL RELEVANCE In this study, we show that hepatocyte growth factor increases drug resistance and metastatic potential of lung cancer cells via focal adhesion kinase activation and apoptosis-inducing factor down-regulation.