title: Ligand-independent activation of EphA2 by arachidonic acid induces metastasis-like behaviour in prostate cancer cells.
abstract: BACKGROUND
  High intake of omega-6 polyunsaturated fatty acids (PUFA) has been associated with clinical progression in prostate cancer (CaP). This study investigates the signalling mechanism by which the omega-6 PUFA arachidonic acid (AA) induces prostatic cellular migration to bone marrow stroma.
  
  
  METHODS
  Western blot analysis of the PC-3, PC3-GFP, DU 145 and LNCaP cells or their lipid raft (LR) components post AA stimulation was conducted in association with assays for adhesion and invasion through the bone marrow endothelial monolayers.
  
  
  RESULTS
  Arachidonic acid increased transendothelial migration of PC3-GFP cells (adhesion 37%±0.08, P=0.0124; transmigration 270%±0.145, P=0.0008). Akt, Src and focal adhesion kinase (FAK) pathways were induced by AA and integrally involved in transendothelial migration. LR were critical in AA uptake and induced Akt activity. Ephrin receptor A2 (EphA2), localised in LR, is expressed in DU 145 and PC-3 cells. Arachidonic acid induced a rapid increase of EphA2 Akt-dependent/ligand-independent activation, while knockdown of the EphrinA1 ligand decreased AA induced transendothelial migration, with an associated decrease in Src and FAK activity. Arachidonic acid activated Akt in EphA2(-) LNCaP cells but failed to induce BMEC transendothelial invasion.
  
  
  CONCLUSIONS
  Arachidonic acid induced stimulation of EphA2 in vitro is associated fundamentally with CaP epithelial migration across the endothelial barrier.
authors.affiliation: Genito Urinary Cancer Research Group, School of Cancer and Enabling Sciences, Paterson Institute for Cancer Research, The University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: T
authors.initials: T
authors.lastname: Tawadros
authors.forename: M D
authors.initials: MD
authors.lastname: Brown
authors.forename: C A
authors.initials: CA
authors.lastname: Hart
authors.forename: N W
authors.initials: NW
authors.lastname: Clarke
mesh_terms: D016718:Arachidonic Acid / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D036382:Ephrin-A1 / Q000235:genetics / Q000378:metabolism; D043371:Fatty Acids, Omega-6 / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016391:Genes, src; D006801:Humans; D008024:Ligands; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D036382:Ephrin-A1; D043371:Fatty Acids, Omega-6; D008024:Ligands; D016718:Arachidonic Acid; D036104:Receptor, EphA2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt