Differential effects of ethanol on insulin-like growth factor-I receptor signaling

Background: Activation of the insulin-like growth factor I receptor (IGF-IR ) by its ligands IGF-I and IGF-II induces cell proliferation and protects a gainst apoptosis. Ethanol inhibits IGF-IR tyrosine autophosphorylation, whi ch subsequently interferes with the activation of key downstream signaling mediators including insulin-receptor substrate-1, phosphatidylinositol 3-ki nase, and mitogen-activated protein (MAP) kinase. The ethanol-induced inhib ition of IGF-IR signaling reduces mitogenesis and enhances apoptosis. In th e current study, we demonstrate that the antiproliferative action of ethano l can be modulated by differential sensitivity of the autophosphorylation o f the IGF-IR to ethanol. Methods: A series of subclones was generated from 3T3 cells that express th e human IGF-IR. Results: There was considerable variability in the ability of ethanol to in hibit IGF-I-dependent IGF-IR tyrosine autophosphorylation and MAP kinase ac tivation, despite equivalent IGF-IR expression. The IGF-TR was completely r esistant to a high concentration of ethanol (150 mM) in several subclones. The sensitivity of IGF-IR autophosphorylation to ethanol correlated directl y with the inhibition of IGF-I-mediated MAP kinase activation and cell prol iferation. Resistant subclones exhibited features of the transformed phenot ype including high MAP kinase activity,partial loss of contact inhibition, and the development of foci at confluency. The IGF-IR isolated from ethanol -resistant cells was similarly resistant to ethanol in autophosphorylation reactions in vitro whereas ethanol inhibited the autophosphorylation of IGF -IR obtained from sensitive cells. Conclusions: Our findings are the first to demonstrate the modulation of et hanol sensitivity of a tyrosine kinase receptor, and they provide a molecul ar basis for differential effects of ethanol on cell proliferation.