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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. [ABSTRACT FROM AUTHOR]

Background:Although statins do not affect the incidence of prostate cancer (CaP), usage reduces the risk of clinical progression and mortality. Although statins are known to downregulate the mevalonate pathway, the mechanism by which statins reduce CaP progression is unknown.Methods:Bone marrow stroma (BMS) was isolated with ethical approval from consenting patients undergoing surgery for non-malignant disease. PC-3 binding, invasion and colony formation within BMS was assessed by standardised in vitro co-culture assays in the presence of different statins.Results:Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1 μM) and rosuvastatin (5 μM), but not pravastatin, significantly reducing invasion towards BMS by an average of 66.68% (range 53.93-77.04%; P<0.05) and significantly reducing both number (76.2±8.29 vs 122.9±2.48; P=0.0055) and size (0.2±0.0058 mm2 vs 0.27±0.012 mm2; P=0.0019) of colonies formed within BMS. Statin-treated colonies displayed a more compact morphology containing cells of a more epithelial phenotype, indicative of a reduction in the migrational ability of PC-3 cells. Normal PC-3 phenotype and invasive ability was recovered by the addition of geranylgeranyl pyrophosphate (GGPP).Conclusion:Lipophilic statins reduce the migration and colony formation of PC-3 cells in human BMS by inhibiting GGPP production, reducing the formation and the spread of metastatic prostate colonies. [ABSTRACT FROM AUTHOR]