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[Cancer Research 57, 1306-1311, April 1, 1997]
© 1997 American Association for Cancer Research
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Activation of Mitogenic Signaling by Endothelin 1 in Ovarian Carcinoma Cells1

Anna Bagnato2, Raffaele Tecce, Valeriana Di Castro and Kevin J. Catt

Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi d'Oro 156–158, 00158, Rome, Italy [A. B., R. T., V. D. C.], and Endocrinology and Reproduction Research Branch, NIH, Bethesda, Maryland 20892 [K. J. C.]

Endothelin 1 (ET-1) is produced in ovarian cancer cell lines and has been shown to act through ETA receptors as an autocrine growth factor to promote tumor cell proliferation in vitro. In OVCA 433 cells, the efficacy of ET-1 as a stimulus of [3H]thymidine incorporation was equivalent to that of epidermal growth factor. ET-1 also stimulated the rapid expression of c-fos, an action mediated by ETA receptors. The mitogenic action of ET-1 was not mediated by a pertussis toxin-sensitive G protein. An analysis of the effects of inhibition and depletion of protein kinase C (PKC) on mitogenic responses demonstrated that PKC was necessary but not sufficient for maximal stimulation by ET-1. In quiescent OVCA 433 cells, ET-1-induced stimulation of [3H]thymidine incorporation was prevented by two structurally distinct inhibitors of tyrosine kinase, herbimycin A and genistein. These results indicate that 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 p125FAK and p42 mitogen-activated protein kinase were identified. The additivity between the potent mitogenic actions of ET-1 and epidermal growth factor is consistent with the independence of their signal transduction pathways in ovarian cancer cells. These findings also indicate that intracellular signaling between the ETA receptor and a yet unidentified tyrosine kinase is involved in the mitogenic response to ET-1.

1 This work was supported in part by grants from the Associazione Italiana Ricerca sul Cancro and Ministero della Sanità.

2 To whom requests for reprints should be addressed.

Received 10/ 1/96. Accepted 2/ 3/97.




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