Potential Antitumor Activity of SIM-89 in Non-Small Cell Lung Cancer Cells.
10.3349/ymj.2017.58.3.581
- Author:
Jun PEI
1
;
Tianqing CHU
;
Minhua SHAO
;
Jiajun TENG
;
Huifang SHA
;
Aiqing GU
;
Rong LI
;
Jialin QIAN
;
Weifeng MAO
;
Ying LI
;
Baohui HAN
Author Information
1. Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. hanbh520@163.com
- Publication Type:Original Article
- Keywords:
c-Met;
antitumor;
cell proliferation;
cell migration;
lung cancer
- MeSH:
Adenosine Triphosphate;
Blotting, Western;
Carcinogenesis;
Carcinoma, Non-Small-Cell Lung*;
Cell Movement;
Cell Proliferation;
Enzyme-Linked Immunosorbent Assay;
Gene Expression;
Hepatocyte Growth Factor;
Lung Neoplasms;
Phosphorylation;
Phosphotransferases;
Protein Kinases;
Protein-Tyrosine Kinases
- From:Yonsei Medical Journal
2017;58(3):581-591
- CountryRepublic of Korea
- Language:English
-
Abstract:
PURPOSE: c-Met and its ligand, hepatocyte growth factor (HGF), play a critical role in oncogenesis and metastatic progression. The aim of this study was to identify inhibited enzymogram and to test the antitumor activity of SIM-89 (a c-Met receptor tyrosine kinase inhibitor) in non-small cell lung cancer. MATERIALS AND METHODS: Z′-LYTE kinase assay was employed to screen the kinase enzymogram, and mechanism of action (MOA) analysis was used to identify the inhibited kinases. Cell proliferation was then analyzed by CCK8 assay, and cell migration was determined by transwell assay. The gene expression and the phosphorylation of c-Met were examined by realtime-PCR and western blotting, respectively. Finally, the secretion of HGF was detected by ELISA assay. RESULTS: c-Met, activated protein kinase (AMPK), and tyrosine kinase A (TRKA) were inhibited by SIM-89 with the IC₅₀ values of 297 nmol/L, 1.31 µmol/L, and 150.2 nmol/L, respectively. SIM-89 exerted adenosine triphosphate (ATP) competitive inhibition on c-Met. Moreover, the expressions of STAT1, JAK1, and c-Met in H460 cells were decreased by SIM-89 treatment, and c-Met phosphorylation was suppressed in A549, H441, H1299, and B16F10 cells by the treatment. In addition, SIM-89 treatment significantly decreased the level of HGF, which accounted for the activation of c-Met receptor tyrosine kinase. Finally, we showed cell proliferation inhibition and cell migration suppression in H460 and H1299 cells after SIM-89 treatment. CONCLUSION: In conclusion, SIM-89 inhibits tumor cell proliferation, migration and HGF autocrine, suggesting it's potential antitumor activity.
