Ethanol promotes cell death by inhibition of the insulin-like growth factor I receptor

被引:41
作者
Cui, SJ [1 ]
Tewari, M [1 ]
Schneider, T [1 ]
Rubin, R [1 ]
机构
[1] THOMAS JEFFERSON UNIV, JEFFERSON MED COLL, DEPT PATHOL ANAT & CELL BIOL, PHILADELPHIA, PA 19107 USA
关键词
ethanol; insulin-like growth factor; tumor necrosis factor; apoptosis;
D O I
10.1111/j.1530-0277.1997.tb04262.x
中图分类号
R194 [卫生标准、卫生检查、医药管理];
学科分类号
摘要
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. 71:657-662, 1994) that ethanol in low concentrations inhibits the tyrosine autophosphorylation 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-alpha (TNF-alpha) model of apoptosis. In serum-depleted medium, IGF-I markedly protected BALB/c3T3 cells from TNF-alpha-induced apoptosis. Ethanol reversed the protective action of IGF-I, but did not enhance TNF-alpha killing in the absence of IGF-I. Half-maximal effective concentrations of ethanol were 5 to 10 mM. In the presence of 5 to 10% fetal bovine serum, TNF-alpha 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.
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页码:1121 / 1127
页数:7
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