Insulin‐like growth factor‐1 protects peroxynitrite‐induced cell death by preventing cytochromec‐induced caspase‐3 activation

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Abstract
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 cytochromecrelease 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 cytochromec. 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 cytochromecto 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 cytochromecrelease through the inhibition of caspase‐3‐like activation. J. Cell. Biochem. 84: 708–716, 2002.