Tumor promoter teleocidin inhibits internalization and nuclear accumulation of epidermal growth factor in cultured human hepatoma cells

Abstract

Teleocidin and its derivative dihydroteleocidin are toxic substances isolated from Streptomyces [ 11. They induce ornithine decarboxylase activity when painted on the skin, cause adhesion of human promyelocytic leukemia cells, inhibit terminal differentiation of Friend erythroleukemia cells, and exert mitogenic effects in cultured human lymphocytes [2-41. In addition, dihydroteleocidin shows potent tumor-promoting activity when applied on mouse skin [4]. The effects of teleocidins are essentially identical to those produced by 12-0-tetradecanoyl-phorbol-13-acetate (TPA), a phorbol ester whose initial site of action is the cell membrane. Furthermore, teleocidins have been shown to interact directly with the receptor for phorbol esters [S], and as TPA [5-71, to inhibit the binding of epidermal growth factor (EGF) to its receptor [5]. Because TPA acts synergistically with most growth factors, it may increase non-selectively cellular sensitivity to any growth factor, or, act through a specific hormonal pathway [6-91; one such pathway may be in certain cell types, that utilized by vasopressin [8]. toma cells. Provided the lysosomal inhibitor chloroquine is present, teleocidin inhibits the internalization and the nuclear association of EGF. These results appear to be of interest for understanding the mechanism of action of both EGF and teleocidin.