Insulin-like growth factor-1 protects peroxynitrite-induced cell death by preventing cytochrome c-induced caspase-3 activation.
We investigated the effect of IGF-1 on cell death induced by peroxynitrite in human neuroblastoma SH-SY5Y cells. Exposure of the cells to 3-morpholinosydnonimine (SIN-1), a peroxynitrite donor, caused cytochrome c release from the mitochondria, caspase-3-like activation, and cell death. Pre-incubation of the cells with the caspase-3 inhibitor partially prevented SIN-1-induced cell death. Simultaneous addition of IGF-1 reduced SIN-1-induced caspase-3-like activation and cell death, whereas IGF-1 failed to reduce the release of cytochrome c. IGF-1 increased Akt phosphorylation, and Akt phosphorylation was inhibited by wortmannin, an inhibitor of phosphatidylinositol 3-kinase. In addition, wortmannin prevented IGF-1-evoked inhibition of cell death and caspase-3-like activation. In a cell-free system, addition of cytochrome c to cytosolic fraction resulted in caspase-3-like activation. The activation was reduced when the cytosolic fraction prepared from IGF-1-treated cells was used. These results suggest that IGF-1 protects peroxynitrite-induced cell death downstream of cytochrome c release through the inhibition of caspase-3-like activation.
Saeki
Makio
M
Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan. msaek@dent.osaka-u.ac.jp
Maeda
Sadaaki
S
Wada
Kouichirou
K
Kamisaki
Yoshinori
Y
D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism* / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; D030421:Peroxynitrous Acid; C002385:linsidomine; D007334:Insulin-Like Growth Factor I; D008981:Molsidomine; D019869:Phosphatidylinositol 3-Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D004298:Dopamine