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Journal of Lipid Research, Vol. 44, 1963-1975, October 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells

Céline Luquain^*, Anurag Singh^*, Lixin Wang, Vishwanathan Natarajan and Andrew J. Morris^1,*

^* Department of Cell and Developmental Biology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7090
Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins University, Baltimore, MD 21224

¹ To whom correspondence should be addressed. e-mail: ajmorris{at}med.unc.edu

Lysophosphatidic acid (LPA) is a receptor-active lipid mediator with a broad range of biological effects. Ovarian cancer cells synthesize LPA, which promotes their motility, growth, and survival. We show that a murine homolog of a human protein previously reported to hydrolyze LPA is a highly selective detergent-stimulated LPA phosphatase that can be used to detect and quantitate LPA. Use of this protein in novel enzymatic assay demonstrates that SK-OV-3 ovarian cancer cells release physiologically relevant levels of biologically active LPA into the extracellular space. LPA release is markedly increased by nucleotide agonists acting through a P2Y₄ purinergic receptor. Promotion of LPA formation by nucleotides is accompanied by stimulation of phospholipase D (PLD) activity. Overexpression of both PLD1 and PLD2 in SK-OV-3 cells produces active enzymes, but only overexpression of PLD2 results in significant amplification of both nucleotide-stimulated PLD activity and LPA production. SK-OV-3 cells express and secrete a phospholipase A₂ activity that can generate LPA from the lipid product of PLD, phosphatidic acid.

Our results identify a novel role for nucleotides in the regulation of ovarian cancer cells and suggest an indirect but critical function for PLD2 in agonist-stimulated LPA production.

Abbreviations: ARF, ADP-ribosylation factor; C1P, ceramide 1-phosphate; LPA, lysophosphatidic acid; LPAP, lysophosphatidic acid phosphatase; LPP, lipid phosphate phosphatase; PA, phosphatidic acid; PC, phosphatidylcholine; PI(4,5)P₂, phosphatidylinositol 4,5-bisphosphate; PLA₂, phospholipase A₂; PLC, phospholipase C; PLD, phospholipase D; PtdBut, phosphatidylbutanol; S1P, sphingosine 1-phosphate

Supplementary key words lysophosphatidic acid phosphatase • enzymatic assay • uridine 5' triphosphate • adenosine 5'-triphosphate • phospholipase D1/phospholipase D2 isoforms • purinergic receptor • phospholipase A₂ • phosphatidic acid • phosphatidylcholine-specific phospholipase D

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