Ethanol-induced inhibition of cell proliferation is modulated by insulin-like growth factor-I receptor levels.
Ethanol inhibits the tyrosine autophosphorylation of the insulin-like growth factor (IGF)-I receptor, an action that correlates with the inhibition of IGF-I-stimulated cell proliferation [J. Biol. Chem. 268:21777-21782 (1993)]. In the current study, the IGF-I-dependent proliferation of mouse BALB/c3T3 cells was completely inhibited by ethanol, but the growth of BALB/c3T3 cells that overexpress the IGF-I receptor (p6 cells) was only partially inhibited by ethanol BALB/ c3T3 cells that simultaneously overexpress both the IGF-I receptor and IGF-I were insensitive to growth inhibition by ethanol. In p6 cells, increasing concentrations of IGF-I overcame the inhibition of IGF-I receptor tyrosine autophosphorylation in the presence of ethanol. The importance of the IGF-I receptor as a specific target for ethanol was further investigated in C6 rat giloblastoma cells that respond mitogenically to both epidermal growth factor (EGF) and IGF-I. The mitogenic response of C6 cells to EGF was abrogated in cells expressing antisense mRNA to the IGF-I receptor. Thus, EGF action in these cells is dependent on activation of an IGF-I/IGF-I receptor autocrine pathway. Indeed, EGF stimulated an increase in IGF-I receptor levels by more than 100%. Ethanol completely inhibited the proliferation of C6 cells in response to either EGF or IGF-I. However, ethanol did not directly interfere with EGF receptor function, because EGF-induced cell proliferation was unaffected by ethanol when added exclusively during a 1-hr exposure to EGF. Ethanol did not interfere with the EGF-induced increase in IGF-I receptor expression. The addition of both EGF and IGF-I overcame the inhibitory action of ethanol. In conclusion, the potency of ethanol as an inhibitor of IGF-I-mediated cell proliferation correlates with the level of IGF-I receptors. In contrast to its effect on the IGF-I-receptor, ethanol has no direct effect on EGF receptor activation.
Resnicoff
M
M
Department of Anatomy, Pathology and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania, USA.
Cui
S
S
Coppola
D
D
Hoek
J B
JB
Rubin
R
R
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology; D000431:Ethanol / Q000633:toxicity*; D005909:Glioblastoma; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000187:drug effects*
D000431:Ethanol; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1