Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 119, Issue 2, Pages 150-159Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1254/jphs.12048FP
Keywords
SU11274; superoxide anion; hydrogen peroxide; c-Met; A549 cell
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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 (O-2(center dot-)) 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. O-2(center dot-) and H2O2 generation activated c-Met-PI3K-Akt and c-Met Grb2/SOS-Ras-p38 signaling pathways, which were suppressed by O-2(center dot-) scavenger superoxide dismutase (SOD) and H2O2 scavenger catalase. In conclusion, O-2(center dot-) 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.
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