Endothelin-1 promotes proteolytic activity of ovarian carcinoma.
Endothelin-1 (ET-1) is a potent mitogenic and angiogenic factor for ovarian carcinoma cell lines, which acts selectively through the ET(A) receptor (ET(A)R). A previous study demonstrated that ET-1 is present at high concentrations in ovarian cancer ascites, indicating a direct role in the progression and metastasis of ovarian carcinoma. In this study, we investigated whether ET-1 could induce production and activation of tumour-associated proteinases in ovarian carcinoma cells. As demonstrated by ELISA, we found that the secretion of matrix metalloproteinase (MMP)-2 and MMP-9, urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 and -2 was upregulated by ET-1 in a dose-dependent manner in the HEY cell line. In addition, the MMPs in ET-1-treated cells are consistently active, as shown by MMP gelatinase activity assay. Finally, we demonstrated that BQ-123, an antagonist of ET(A)R, inhibited the ET-1-induced tumour protease secretion and activity, suggesting that ET-1/ET(A)R may play an important role in the progression and metastasis of ovarian carcinoma, activating multiple proteinase cascades.
Laboratory of Molecular Pathology, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.
Laura
L
Rosanò
Debora
D
Salani
Valeriana
V
Di Castro
Francesca
F
Spinella
Pier Giorgio
PG
Natali
Anna
A
Bagnato
D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000627:therapeutic use; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism; D044022:Receptor, Endothelin A; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D044022:Receptor, Endothelin A; D010450:Endopeptidases; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C072247:cyclo(Trp-Asp-Pro-Val-Leu)