Inhibition of Cyclooxygenase-1 and -2 Expression by Targeting the Endothelin A Receptor in Human Ovarian Carcinoma Cells

Purpose and Experimental Design: New therapies against cancer are based on targeting cyclooxygenase (COX)-2. Activation of the endothelin A receptor (ETAR) by endothelin (ET)-1 is biologically relevant in several malignancies, including ovarian carcinoma. In this tumor, the ET-1/ETAR autocrine pathway promotes mitogenesis, apoptosis protection, invasion, and neoangiogenesis. Because COX-1 and COX-2 are involved in ovarian carcinoma progression, we investigated whether ET-1 induced COX-1 and COX-2 expression through the ETAR at the mRNA and protein level in HEY and OVCA 433 ovarian carcinoma cell lines by Northern blot, reverse transcription-PCR, Western blot, and immunohistochemistry; we also investigated the activity of the COX-2 promoter by luciferase assay and the release of prostaglandin (PG) E2 by ELISA. Results: ET-1 significantly increases the expression of COX-1 and COX-2, COX-2 promoter activity, and PGE2 production. These effects depend on ETAR activation and involve multiple mitogen-activated protein kinase (MAPK) signaling pathways, including p42/44 MAPK, p38 MAPK, and transactivation of the epidermal growth factor receptor. COX-2 inhibitors and, in part, COX-1 inhibitor blocked ET-1-induced PGE2 and vascular endothelial growth factor release, indicating that both enzymes participate in PGE2 production to a different extent. Moreover, inhibition of human ovarian tumor growth in nude mice after treatment with the potent ETAR-selective antagonist ABT-627 is associated with reduced COX-2 and vascular endothelial growth factor expression. Conclusions: These results indicate that impairing COX-1 and COX-2 and their downstream effect by targeting ETAR can be therapeutically advantageous in ovarian carcinoma treatment. Pharmacological blockade of the ETAR is an attractive strategy to control COX-2 induction, which has been associated with ovarian carcinoma progression and chemoresistance.

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