Epidermal growth factor, like phorbol esters, induces plasminogen activator in HeLa cells

Abstract

STUDIES on the action of the tumour-promoting compound 12-O-tetradecanoyl-phorbol-13-acetate (TPA), and related plant diterpenes, in cell culture systems have revealed several unusual biological properties^1–3. These include the induction of plasminogen activator production² as well as several other phenotypic changes resembling those seen in cells transformed by chemical carcinogens or viruses¹. Furthermore, these compounds are extremely potent inhibitors of several types of terminal differentiation^1,4,5, all these effects being exerted by very low concentrations of the active compounds, in the range of 10⁻⁹M. In addition, the activities of a series of such compounds, with respect to their cell culture effects, in general parallel their activities as promoters in the mouse skin two-stage carcinogenesis system^1,6. We have previously postulated that the highly pleiotropic effects of these compounds may be due to their ability to usurp the effector system of an endogenous growth regulatory hormone^1,3,7,8. The polypeptide hormone epidermal growth factor (EOF) is a possible candidate for this putative substance as it shares several biological properties with the phorbol esters^9–14. Consistent with this hypothesis are recent results from our laboratory indicating that TPA is a potent inhibitor of the binding of ¹²⁵I-EGF to its cellular receptors³. We report here that EGF and TPA resemble each other in their ability to serve as potent inducers of plasminogen activator production in HeLa cell cultures. Our results further suggest that the mechanism of EGF induction ot this protease is also similar to that of induction produced by TPA and related tumour promoters.