Azoxymethane enhances ligand-induced activation of EGF receptor tyrosine kinase in the colonic mucosa of rats

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Abstract
Recent observations suggest that transforming growth facto α (TGF-α), which binds to the epidermal growthfacto (EGF) receptor (EGFR), may induce neoplastic growth of the colonic mucosa through an autocrine mechanism. To assess the functional role of TGF-α in colonic carcinogenesis the present investigation examines the changes in TGF-α and EGF-induced activation of intrinsic tyrosine kinase (Tyr-k) activity of EGFR in the colonic mucosa of rats after administration of the colonic carcinogen azoxymethan(AOM; 20 mg/kg body wt). Five days after a single injection of AOM to 4-to 5-month old rats proliferative activity (assessed by 5-bromo-2'-deoxyuridine immunoreactivity) in the colonic mucosa was increased by ∼700% over the corresponding saline-injected controls. This was accompanied by: (i) a marked rise in autophosphorylation of a number of mucosal proteins, including one with a Mr of170 kDa, a molecular mass that corresponds to EGFR; (ii) a 110-130% increase in basal EGFR Tyr-k activity, Despit this rise in basal EGFR Tyr-k activity, exposure of isolated colonocytes or detergent-solubilized colonic mucosa from AOM-treated animals to either 1×10−8 M TGF-α or EGF caused a further 90-160% increase increase in EGFR Tyr-k activity over the corresponding basal levels. In contrast, bombesir produced no apparent change in EGFR Tyr-k activity. We conclude that increased ligand-induced activation of EGFR Tyr-k may be an important event for development of the hyperproliferative state associated with induction of colorectal neoplasia.

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