Endothelin-1 stimulates cyclooxygenase-2 expression in ovarian cancer cells through multiple signaling pathways: evidence for involvement of transactivation of the epidermal growth factor receptor.
Ovarian carcinoma cells release high amounts of endothelin-1 and exhibit increased expression of endothelin-A receptor. Engagement of the endothelin-A receptor triggers tumor growth, survival, neoangiogenesis and invasion. Cyclooxygenase-1 and cyclooxygenase-2 are enzymes involved in the production of prostaglandins and play a role in the regulation of tumor progression in several malignancies, including ovarian carcinomas. Endothelin-1 significantly increases the expression of cyclooxygenase-1 and cyclooxygenase-2 mRNA and protein, the activity of the cyclooxygenase- 2 promoter, and the release of prostaglandin E2 from two ovarian carcinoma cell lines, HEY and OVCA 433. The cyclooxygenase- 2 inhibitor, NS-398 drastically decreased the endothelin- 1-induced prostaglandin E2 production and vascular endothelial growth factor upregulation, indicating a role for cyclooxygenase-2 in endothelin-1-induced vascular endothelial growth factor-mediated angiogenesis. In this study we demonstrated that endothelin-1-induced cyclooxygenase-2 and related prostaglandin E2 release were dependent upon the activation of endothelin-A receptor and of multiple mitogen-activated protein kinase signal pathways, including extracellular signal-regulated kinase 1/2 kinase, p38 mitogen-activated protein kinase and the transactivation of the epidermal growth factor receptor. In human ovarian xenografts, the levels of cyclooxygenase-2 protein expression were significantly reduced following treatment with the endothelin-A receptor selective antagonist, atrasentan, compared with untreated mice. These results suggest that the pharmacological blocking of endothelin-A receptor is an attractive strategy to control the cyclooxygenase-2 protein expression in ovarian carcinoma.
Spinella
Francesca
F
Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Rome, Italy.
Rosanò
Laura
L
Elia
Giacomo
G
Di Castro
Valeriana
V
Natali
Pier Giorgio
PG
Bagnato
Anna
A
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004790:Enzyme Induction; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010456:Peptides, Cyclic / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D005419:Flavonoids; D007093:Imidazoles; D010456:Peptides, Cyclic; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D044022:Receptor, Endothelin A; D020032:Tyrphostins; C101044:RTKI cpd; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093642:SB 203580; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one