Ligand-independent activation of EphA2 by arachidonic acid induces metastasis-like behaviour in prostate cancer cells

• Published in: British journal of cancer Vol. 107; no. 10; pp. 1737 - 1744
• Main Authors: Tawadros, T, Brown, M D, Hart, C A, Clarke, N W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.11.2012; Nature Publishing Group
• Subjects: 631/45/287/1183; 631/80/86; 692/699/67/322; 692/699/67/589/466; Adipocytes; Arachidonic Acid - pharmacology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cancer Research; Cell culture; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cloning; Drug Resistance; Endothelium - metabolism; Endothelium - pathology; Ephrin-A1 - genetics; Ephrin-A1 - metabolism; Epidemiology; Fatty Acids, Omega-6 - pharmacology; Focal Adhesion Protein-Tyrosine Kinases - genetics; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Genes, src; Humans; Kinases; Ligands; Male; Medical prognosis; Medical research; Medical sciences; Mesenchymal Stromal Cells - metabolism; Mesenchymal Stromal Cells - pathology; Metastasis; Molecular Diagnostics; Molecular Medicine; Neoplasm Metastasis; Nephrology. Urinary tract diseases; Oncology; Phosphorylation; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptor, EphA2 - genetics; Receptor, EphA2 - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; United Kingdom > UK; omega-6; prostate cancer; bone marrow stroma; metastasis; bone marrow endothelial cells; Ephrin A2; Endothelial cell; Urinary system disease; Ephrin; Prostate disease; Ligand; Prostate metastasis; Stroma; trk receptor; Malignant tumor; Arachidonic acid; Cancerology; Bone marrow; Male genital diseases; Prostate cancer; Tumor cell; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.457

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. Conclusion: Arachidonic acid induced stimulation of EphA2 in vitro is associated fundamentally with CaP epithelial migration across the endothelial barrier.