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Lysophosphatidic Acid Is Constitutively Produced by Human Peritoneal Mesothelial Cells and Enhances Adhesion, Migration, and Invasion of Ovarian Cancer Cells

¹ Department of Cancer Biology, Lerner Research Institute and ² Department of Gynecology and Obstetrics, The Cleveland Clinic Foundation, Cleveland, Ohio; ³ Echelon Biosciences, Inc.; and ⁴ Department of Medicinal Chemistry, The University of Utah, Salt Lake City, Utah

Requests for reprints: Yan Xu, Department of Obstetrics and Gynecology, Indiana University, 975 W. Walnut St. IB355A, Indianapolis, IN 46202. Fax: 317-278-2884; E-mail: Xu2{at}iupui.edu.

Lysophosphatidic acid (LPA) is both a potential marker and a therapeutic target for ovarian cancer. It is critical to identify the sources of elevated LPA levels in ascites and blood of patients with ovarian cancer. We show here that human peritoneal mesothelial cells constitutively produce LPA, which accounts for a significant portion of the chemotactic activity of the conditioned medium from peritoneal mesothelial cells to ovarian cancer cells. Both production of LPA by peritoneal mesothelial cells and the chemotactic activity in the conditioned medium can be blocked by HELSS [an inhibitor of the calcium-independent phospholipase A₂ (iPLA₂)] and AACOCF₃ [an inhibitor of both cytosolic PLA₂ (cPLA₂) and iPLA₂]. Moreover, cell-based enzymatic activity assays for PLA₂ indicate that peritoneal mesothelial cells have strong constitutive PLA₂ activity. Receptors for LPA, LPA₂, and LPA₃ are involved in the conditioned medium–induced chemotactic activity. Invasion of ovarian cancer cells into peritoneal mesothelial cells has also been analyzed and shown to require PLA₂, LPA receptors, and the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. Thus, we show here, for the first time, that human peritoneal mesothelial cells constitutively produce bioactive lipid signaling molecules, such as LPA, via iPLA₂ and/or cPLA₂ activities. Conditioned medium from peritoneal mesothelial cells stimulate migration, adhesion, and invasion of ovarian cancer cells, and may play similar roles in vivo. (Cancer Res 2006; 66(6): 3006-14)

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