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J Cell Biochem. 2002;84(4):708-16.

Insulin-like growth factor-1 protects peroxynitrite-induced cell death by preventing cytochrome c-induced caspase-3 activation.

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Department of Pharmacology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.


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.

[Indexed for MEDLINE]

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