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. 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.
Cui
S J
SJ
Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania, USA.
Tewari
M
M
Schneider
T
T
Rubin
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D002461:Cell Line, Transformed; D004622:Embryo, Mammalian; D000431:Ethanol / Q000633:toxicity*; D005347:Fibroblasts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008854:Microscopy, Electron; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D017526:Receptor, IGF Type 1