Abstract
Increased expression of autotaxin in tumors including glioblastoma, breast, renal, ovarian, lung, and thyroid cancers is associated with increased tumor aggressiveness. Autotaxin promotes metastasis as well as cell growth, survival, and migration of cancer cells. These actions could depend on the noncatalytic effects of autotaxin on cell adhesion, or the catalytic activity of autotaxin, which converts lysophosphatidylcholine into lysophosphatidate in the extracellular fluid surrounding the tumor. Both lysophosphatidylcholine (LPC) and lysophosphatidate have been reported to stimulate migration through their respective G-protein coupled receptors. The present study determines the roles of autotaxin, LPC, and lysophosphatidate in controlling the migration of two cancer cell lines: MDA-MB-231 breast cancer cells, which produce little autotaxin and MDA-MB-435 melanoma cells that secrete significant levels of autotaxin. LPC alone was unable to stimulate the migration of either cell type unless autotaxin was present. Knocking down autotaxin secretion, or inhibiting its catalytic activity, blocked cell migration by preventing lysophosphatidate production and the subsequent activation of LPA(1/3) receptors. We conclude that inhibiting autotaxin production or activity could provide a beneficial adjuvant to chemotherapy for preventing tumor growth and metastasis in patients with high autotaxin expression in their tumors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anilides / pharmacology
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Catalysis / drug effects
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Cell Line
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Cell Line, Tumor
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Cell Movement / drug effects*
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Cell Movement / genetics
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Cell Movement / physiology
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Enzyme Inhibitors / pharmacology
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Humans
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Kinetics
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Lysophosphatidylcholines / metabolism
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Lysophosphatidylcholines / pharmacology*
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Lysophospholipids / metabolism
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Melanoma / genetics
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Melanoma / metabolism
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Melanoma / pathology
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / genetics
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Multienzyme Complexes / metabolism*
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Organophosphates / pharmacology
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Organophosphonates / pharmacology
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Phosphodiesterase I / antagonists & inhibitors
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Phosphodiesterase I / genetics
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Phosphodiesterase I / metabolism*
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Phosphoric Diester Hydrolases
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Pyridines / pharmacology
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Pyrophosphatases / antagonists & inhibitors
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Pyrophosphatases / genetics
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Pyrophosphatases / metabolism*
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RNA Interference
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RNA, Small Interfering / genetics
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Receptors, Lysophosphatidic Acid / antagonists & inhibitors
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Reverse Transcriptase Polymerase Chain Reaction
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Transfection
Substances
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(4-(tetradecanoylamino)benzyl)phosphonic acid
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Anilides
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Enzyme Inhibitors
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Lysophosphatidylcholines
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Lysophospholipids
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Multienzyme Complexes
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Organophosphates
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Organophosphonates
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Pyridines
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RNA, Small Interfering
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Receptors, Lysophosphatidic Acid
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VPC32183
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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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lysophosphatidic acid