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.