Abstract
Important roles for vascular endothelial growth factor (VEGF) and autotaxin (ATX) have been established for embryonic vasculogenesis and cancer progression. We examined whether these two angiogenic factors cooperate in regulation of endothelial cell migratory responses. VEGF stimulated expression of ATX and LPA1, a receptor for the ATX enzymatic product lysophosphatidic acid (LPA), in human umbilical vein endothelial cells. Knockdown of ATX expression significantly decreased mRNA levels for the receptors LPA1, LPA2, S1P1, S1P2, S1P3, and VEGFR2 and abolished cell migration to lysophosphatidylcholine, LPA, recombinant ATX, and VEGF. Migration to sphingosylphosphorylcholine and sphinogosine-1-phosphate was also reduced in ATX knockdown cells, whereas migration to serum remained unchanged. Furthermore, ATX knockdown decreased Akt2 mRNA levels, whereas LPA treatment strongly stimulated Akt2 expression. We propose that VEGF stimulates LPA production by inducing ATX expression. VEGF also increases LPA1 signaling, which in turn increases Akt2 expression. Akt2 is strongly associated with cancer progression, cellular migration, and promotion of epithelial-mesenchymal transition. These data show a role for ATX in maintaining expression of receptors required for VEGF and lysophospholipids to accelerate angiogenesis. Because VEGF and ATX are upregulated in many cancers, the regulatory mechanism proposed in these studies could apply to cancer-related angiogenesis and cancer progression. These data further suggest that ATX could be a prognostic factor or a target for therapeutic intervention in several cancers.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Cell Movement / drug effects
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Cell Movement / physiology*
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Cells, Cultured
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism*
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Humans
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Multienzyme Complexes / drug effects
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Multienzyme Complexes / genetics
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Multienzyme Complexes / metabolism*
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / physiopathology
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Phosphodiesterase I / drug effects
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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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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrophosphatases / drug effects
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Pyrophosphatases / genetics
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Pyrophosphatases / metabolism*
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RNA Interference / physiology
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Receptors, Lysophosphatidic Acid / drug effects
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Receptors, Lysophosphatidic Acid / metabolism*
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Receptors, Lysosphingolipid / drug effects
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Receptors, Lysosphingolipid / metabolism
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Receptors, Vascular Endothelial Growth Factor / drug effects
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Up-Regulation / drug effects
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Up-Regulation / physiology
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor A / pharmacology
Substances
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Multienzyme Complexes
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RNA, Messenger
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Receptors, Lysophosphatidic Acid
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Receptors, Lysosphingolipid
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Receptors, Vascular Endothelial Growth Factor
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AKT2 protein, human
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Proto-Oncogene Proteins c-akt
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Phosphoric Diester Hydrolases
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Phosphodiesterase I
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alkylglycerophosphoethanolamine phosphodiesterase
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Pyrophosphatases