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Ethanol Promotes Cell Death by Inhibition of the Insulin‐Like Growth Factor I Receptor
Author(s) -
Cui Shijun,
Tewari Manorama,
Schneider Tim,
Rubin Raphael
Publication year - 1997
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1997.tb04262.x
Subject(s) - apoptosis , tumor necrosis factor alpha , receptor , growth factor , insulin like growth factor , cell growth , microbiology and biotechnology , programmed cell death , cell culture , chemistry , cytotoxic t cell , fetal bovine serum , cytotoxicity , biology , cell , endocrinology , biochemistry , in vitro , genetics
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.