Activation of mitogenic signaling by endothelin 1 in ovarian carcinoma cells.
Endothelin 1 (ET-1) is produced in ovarian cancer cell lines and has been shown to act through ET(A) 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 ET(A) 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 ET(A) receptor and a yet unidentified tyrosine kinase is involved in the mitogenic response to ET-1.
Bagnato
A
A
Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Rome, Italy.
Tecce
R
R
Di Castro
V
V
Catt
K J
KJ
D016227:Benzoquinones; D015152:Blotting, Northern; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D019833:Genistein; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008301:Maleimides / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000473:pathology*; D037342:Pertussis Toxin; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D016227:Benzoquinones; D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007211:Indoles; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D008301:Maleimides; D011809:Quinones; D010566:Virulence Factors, Bordetella; D017828:Rifabutin; D004815:Epidermal Growth Factor; C020754:herbimycin; D019833:Genistein; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C070515:bisindolylmaleimide I