ACTIVATION OF MITOGENIC SIGNALING BY ENDOTHELIN-1 IN OVARIAN-CARCINOMA CELLS

Endothelin 1 (ET-1) is produced in ovarian cancer cell lines and has b een shown to act through ET(A) receptors as an autocrine growth factor to promote tumor cell proliferation irt vitro. In OVCA 433 cells, the efficacy of ET-1 as a stimulus of [H-3]thymidine incorporation was eq uivalent to that of epidermal growth factor, ET-1 also stimulated the rapid expression of c-fos, an action mediated by ET(A) receptors. The mitogenic action of ET-1 was not mediated by a pertussis toxin-sensiti ve G protein, An analysis of the effects of inhibition and depletion o f protein kinase C (PKC) on mitogenic responses demonstrated that PKC was necessary but not sufficient for maximal stimulation by ET-1. In q uiescent OVCA 433 cells, ET-1-induced stimulation of [H-3]thymidine in corporation was prevented by two structurally distinct inhibitors of t yrosine kinase, herbimycin A and genistein, These results indicate tha t both PKC and protein tyrosine kinase participate in ET-1-stimulated mitogenic signaling, ET-1 rapidly stimulated tyrosine phosphorylation of several cellular proteins, among which p125(FAK) and p42 mitogen-ac tivated protein kinase were identified, The additivity between the pot ent mitogenic actions of ET-1 and epidermal growth factor is consisten t with the independence of their signal transduction pathways in ovari an cancer cells. These findings also indicate that intracellular signa ling between the ET(A) receptor and a yet unidentified tyrosine kinase is involved in the mitogenic response to ET-1.