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

• Main Authors: Ying Liu (Author), Qi-Feng Shi (Author), Yuan-Chao Ye (Author), Shin-ichi Tashiro (Author), Satoshi Onodera (Author), Takashi Ikejima (Author)
• Format: Book
• Published: Elsevier, 2012-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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. Keywords:: SU11274, superoxide anion, hydrogen peroxide, c-Met, A549 cell

Item Description

1347-8613
10.1254/jphs.12048FP