Ethanol Promotes Cell Death by Inhibition of the Insulin-Like Growth Factor I Receptor

The mechanism by which chronic alcohol abuse induces widespread cell and tissue damage is unknown. Insulin-like growth factor I (IGF-I) is an important inhibitor of apoptosis in many cell types, in addition to its ability to stimulate proliferation. We have demonstrated previously (J, Biol. Chem . 268:21777–21782,1993; Lab. Invest . 71657–662, 1994) that ethanol in low concentrations inhibits the tyrosine auto-phosphorylation of the IGF-I receptor (IGF-IR) and IGF-I-mediated cell proliferation. We now demonstrate that ethanol reverses the antiapoptotic action of the IGF-IR in a tumor necrosis factor-a (TNF-α) model of apoptosis. In serum-depleted medium, IGF-I markedly protected BALB/c3T3 cells from TNF-α-induced apoptosis. Ethanol reversed the protective action of IGF-I, but did not enhance TNF-α killing in the absence of IGF-I. Hatf-maximal effective concentrations of ethanol were 5 to 10 mM. In the presence of 5 to 10% fetal bovine serum, TNF-α was cytotoxic for 3T3 cells only in the presence of ethanol. Mouse embryo fibroblasts with targeted knockout of the IGF-IR were completely insensitive to ethanol, in contrast with the ethanol-induced potentiation of apoptosis in wild-type cells. These results indicate that ethanol directly interacts with cellular factors that inhibit apoptosis and could provide a novel mechanism for ethanol-induced cytotoxicity in general.