Abstract
Autotaxin (ATX) is a tumor cell motility-stimulating factor originally isolated from melanoma cell supernatant that has been implicated in regulation of invasive and metastatic properties of cancer cells. Recently, we showed that ATX is identical to lysophospholipase D, which converts lysophosphatidylcholine to a potent bioactive phospholipid mediator, lysophosphatidic acid (LPA), raising the possibility that autocrine or paracrine production of LPA by ATX contributes to tumor cell motility. Here we demonstrate that LPA and ATX mediate cell motility-stimulating activity through the LPA receptor, LPA(1). In fibroblasts isolated from lpa(1)(-/-) mice, but not from wild-type or lpa(2)(-/-), cell motility stimulated with LPA and ATX was completely absent. In the lpa(1)(-/-) cells, LPA-stimulated lamellipodia formation was markedly diminished with a concomitant decrease in Rac1 activation. LPA stimulated the motility of multiple human cancer cell lines expressing LPA(1), and the motility was attenuated by an LPA(1)-selective antagonist, Ki16425. The present study suggests that ATX and LPA(1) represent potential targets for cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium / metabolism
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Cell Line
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Cell Line, Tumor
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Cell Movement
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Cells, Cultured
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Chemotaxis
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Dose-Response Relationship, Drug
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Fibroblasts / metabolism
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Glucose-6-Phosphate Isomerase / physiology*
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Glycoproteins / physiology*
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Isoxazoles / pharmacology
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Lysophospholipids / metabolism*
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Lysophospholipids / physiology*
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Mice
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Mice, Knockout
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Mice, Transgenic
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Microscopy, Fluorescence
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Models, Biological
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Multienzyme Complexes / physiology*
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Neoplasms / metabolism
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Phosphodiesterase I
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Phosphoric Diester Hydrolases / metabolism
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Platelet-Derived Growth Factor / pharmacology
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Propionates / pharmacology
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Pyrophosphatases
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Skin / cytology
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Time Factors
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rac1 GTP-Binding Protein / metabolism
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rhoA GTP-Binding Protein / metabolism
Substances
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3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid
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Glycoproteins
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Isoxazoles
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Lysophospholipids
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Multienzyme Complexes
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Platelet-Derived Growth Factor
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Propionates
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Phosphoric Diester Hydrolases
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Phosphodiesterase I
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alkylglycerophosphoethanolamine phosphodiesterase
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Pyrophosphatases
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rac1 GTP-Binding Protein
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rhoA GTP-Binding Protein
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Glucose-6-Phosphate Isomerase
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lysophosphatidic acid
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Calcium