title: Autotaxin signaling via lysophosphatidic acid receptors contributes to vascular endothelial growth factor-induced endothelial cell migration.
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.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1500, USA.
authors.forename: Malgorzata M
authors.initials: MM
authors.lastname: Ptaszynska
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pendrak
authors.forename: Mary L
authors.initials: ML
authors.lastname: Stracke
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D043264:Phosphodiesterase I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011755:Pyrophosphatases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000187:drug effects / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000187:drug effects / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology; D000099189:Lysophospholipase D
chemical_list: D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D011755:Pyrophosphatases; D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; D049349:Receptors, Lysosphingolipid; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D000099189:Lysophospholipase D; C467484:VEGFA protein, human; C494921:AKT2 protein, human