Tumor promoters block tyrosine-specific phosphorylation of the epidermal growth factor receptor.

Abstract

Tyr-specific phosphorylation of the epidermal growth factor (EGF) receptor in hormonally stimulated A431 cells is blocked by 3 chemically distinct classes of tumor promoters. Tumor-promoting esters of the diterpene phorbol (phorbol 12-myristate 13-acetate, .beta.-phorbol 12,13-dibutyrate and .beta.-phorbol 12,13-didecanoate), indole alkaloids (teleocidin and lyngbyatoxin A) and polyacetates (aplysiatoxin and debromoaplysiatoxin) all inhibited EGF-stimulated phosphorylation of the receptor. Non-tumor-promoting analogs (.beta.-phorbol, .alpha.-phorbol 12,13-didecanoate and hydrolyzed teleocidin) had no effect on the levels of receptor phosphorylation. The ED50 values of the inhibitory effect (0.1-3 ng/ml) reflected the relative tumor-promoting abilities of these compounds in vivo. None of the tumor promoters tested significantly decreased the overall specific binding of 125I-labeled EGF to A431 cells. Scatchard analysis revealed 2 apparent EGF receptors in this cell type. The dose-responses for tumor-promter inhibition of EGF receptor Tyr phosphorylation and high-affinity EGF binding were similar, suggesting that the same initial event is responsible for both effects. This demonstrates a correlation between modulation of EGF receptor binding and phosphorylation of Tyr by tumor promoters. The data suggest a possible role for protein kinase C, the putative cellular receptor for these tumor promoters, in the mechanism of action.