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.
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.
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China.
Ying
Y
Liu
Qi-Feng
QF
Shi
Yuan-Chao
YC
Ye
Shin-ichi
S
Tashiro
Satoshi
S
Onodera
Takashi
T
Ikejima
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D017173:Caenorhabditis elegans; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020839:Son of Sevenless Protein, Drosophila / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D000970:Antineoplastic Agents; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D007211:Indoles; D010879:Piperazines; D020839:Son of Sevenless Protein, Drosophila; D013449:Sulfonamides; D013481:Superoxides; D006861:Hydrogen Peroxide; D002374:Catalase; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins