Activated O2•− and H2O2 Mediated Cell Survival in SU11274-Treated Non-Small-Cell Lung Cancer A549 Cells via c-Met–PI3K–Akt and c-Met–Grb2/SOS–Ras–p38 Pathways

Journal of Pharmacological Sciences

Satoshi Onodera²  Takashi Ikejima¹  Ying Liu¹  Shin-ichi Tashiro²  Yuan-Chao Ye¹  Qi-Feng Shi¹ 

[1] China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, PR China;Department of Clinical and Biomedical Science, Showa Pharmaceutical University, Japan

关键词: SU11274;    superoxide anion;    hydrogen peroxide;    c-Met;    A549 cell;   

DOI  :  10.1254/jphs.12048FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(54)Cited-By(6)The pharmacological activity of SU11274 is primarily due to its inhibition of hepotocyte growth factor receptor (c-Met) kinase overexpression. In this study, we demonstrated that the pathway involved in SU11274-induced autophagy was presumably through inhibition of c-Met and its down-stream pathways, including phosphatidylinositol 3-kinases – Akt (PI3K–Akt) and the growth factor receptor bound protein-2 / son of sevenless – Ras – p38 MAPK (Grb2/SOS–Ras–p38) pathway. SU11274 time-dependently induced the generation of superoxide anion (O2•−) and hydrogen peroxide (H2O2). There is a negative feedback loop between reactive oxygen species (ROS) induction and SU11274. Then, we investigated the role of ROS in protecting cells against SU11274-induced autophagic cell death in A549 cells. O2•− and H2O2 generation activated c-Met–PI3K–Akt and c-Met–Grb2/SOS–Ras–p38 signaling pathways, which were suppressed by O2•− scavenger superoxide dismutase (SOD) and H2O2 scavenger catalase. In conclusion, O2•− and H2O2 evoked cell resistance to SU11274 via activating c-Met–PI3K–Akt and c-Met–Grb2/SOS–Ras–p38 pathways in A549 cells. SU11274 also induced ROS generation in Caenorhabditis elegans.

【 授权许可】

Unknown