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Cyclooxygenase-2 Functions as a Downstream Mediator of Lysophosphatidic Acid to Promote Aggressive Behavior in Ovarian Carcinoma Cells

Departments of ¹ Cell and Molecular Biology and ² Pathology; ³ Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois; ⁴ Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada; and ⁵ College of Pharmacy, University of New Mexico, Albuquerque, New Mexico

Requests for reprints: M. Sharon Stack, Department of Cell and Molecular Biology, Northwestern University, 303 East Chicago Avenue, Tarry 8-715, Chicago, IL 60611. Phone: 312-908-8216; Fax: 312-503-7912; E-mail: mss130{at}northwestern.edu.

Elevated levels of the bioactive lipid lysophosphatidic acid (LPA) are detectable in the majority of patients with both early- and late-stage ovarian cancer, suggesting that LPA promotes early events in ovarian carcinoma dissemination. LPA contributes to the development, progression, and metastasis of ovarian cancer in part by inducing the expression of genes that contribute to proliferation, survival, or invasion, including cyclooxgenase-2 (COX-2) and matrix metalloproteinase–2 (MMP-2). We have previously shown that LPA promotes proMMP-2 activation and MMP-2–dependent migration and invasion in ovarian cancer cells. The purpose of the current study was to determine whether the effect of LPA on acquisition of the metastatic phenotype in ovarian cancer cells is mediated via a COX-2–dependent mechanism. Immunohistochemical analysis of 173 ovarian tumors showed strong COX-2 immunoreactivity in 63% of tumor specimens, including 50% of borderline tumors. LPA increased COX-2 protein expression in a time- and concentration-dependent manner in two of three immortalized borderline ovarian epithelial cells as well as in four of six ovarian cancer cell lines. This was accomplished by both activation of the Edg/LPA receptor and LPA-mediated transactivation of the epidermal growth factor receptor, which increased COX-2 expression via the Ras/mitogen-activated protein kinase pathway. COX-2 also played a role in LPA-induced invasion and migration, as treatment with the COX-2 specific inhibitor NS-398 reduced LPA-induced proMMP-2 protein expression and activation and blocked MMP-dependent motility and invasive activity. These data show that COX-2 functions as a downstream mediator of LPA to potentiate aggressive cellular behavior.

Key Words: Ovarian cancer • Cyclooxgenase-2 • Lysophosphatidic acid • Matrix metalloproteinase

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