ETHANOL INHIBITS INSULIN-LIKE GROWTH FACTOR-1-MEDIATED SIGNALING AND PROLIFERATION OF C6 RAT GLIOBLASTOMA CELLS

BACKGROUND: Alcohol consumption during pregnancy often results in diso rders of fetal development (Fetal Alcohol Syndrome). The brain appears to be particularly vulnerable, and alcohol abuse during pregnancy is probably the most common cause of acquired mental retardation. We ther efore studied the in vitro effects of ethanol on insulin-like growth f actor-1 (IGF-1)-mediated proliferation of rat C6 glioblastoma cells. E XPERIMENTAL DESIGN: The proliferation of C6 rat glioblastoma cells was measured in serum-free medium supplemented with specific growth facto rs in the presence or absence of ethanol. The effect of ethanol on IGF -1 receptor and insulin receptor substrate 1 (IRS-1) tyrosine phosphor ylation was determined by immunoprecipitation and Western blotting, as was the phosphatidylinositol S-kinase content within IRS-1 immunoprec ipitates. RESULTS: C6 cells grew slowly in serum-free medium and proli ferated in response to IGF-1. Ethanol, at physiologically tolerated co ncentrations, markedly inhibited the growth of C6 cells in response to IGF-1, but had no effect on the proliferative rate in the presence of platelet-derived growth factor or 1% fetal bovine serum. Inhibition o f cell proliferation was evident when ethanol was only present during a 1-hour pulse of IGF-1. Cell growth in the presence of IGF-2 was also prevented by ethanol. The inhibition of IGF-1-mediated cell prolifera tion was accompanied by abrogation of IGF-1 receptor tyrosine autophos phorylation. Ethanol also interfered with the IGF-1-induced tyrosine p hosphorylation of IRS-1, and the association of phosphatidylinositol-3 kinase with IRS-1. CONCLUSIONS: The data indicate that physiologicall y relevant concentrations of ethanol inhibit the responses of glial ce lls to IGF-1, including IGF-1 receptor autophosphorylation, IRS-1 and phosphatidylinositol-3 kinase activation, and cell growth.