Etiology and Pathogenesis > Epidermal Growth Factor · Insulin-like Growth Factors

Abstract

Ethanol-induced inhibition of cell proliferation is modulated by insulin-like growth factor-I receptor levels

Resnicoff M, Cui S, Coppola D, Hoek JB, Rubin R

Department of Anatomy, Pathology and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania, USA

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.

PMID: 8865975 [PubMed - indexed for MEDLINE]