Vascular endothelial growth factor production in human prostate cancer cells is stimulated by overexpression of platelet 12-lipoxygenase

BACKGROUND. Elevated platelet 12-Lipoxygenase (P12-LOX) expression is associated with advanced stage and grade prostate cancer and overexpression in PC-3 cells promotes tumor growth and angiogenesis. The mechanisms underlying the role of P12-LOX in angiogenesis remain unclear. METHODS. Enzyme linked immunosorbent assays were used to measure 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) and vascular endothelial growth factor (VEGF) in conditioned media of PC-3 cells stably overexpressing human P12-LOX. Immunoblotting was used to observe stimulation of signal transduction in prostate cancer cell lines following exposure to 12(S)-HETE. RESULTS. P12-LOX overexpression promotes increased accumulation of 12(S)-HETE and VEGF in cult-Lire media leading to constitutive ERK1/2 phosphorylation. 12(S)-HETE stimulates ERK1/2 phosphorylation via a pertussis toxin sensitive G-protein coupled receptor (GPCR) and MEK; the inhibition of which reduces VEGF accumulation by 36% and 70%, respectively. CONCLUSIONS. Our data provide insight into a possible mechanism by which prostate cancer cells with elevated expression of P12-LOX stimulate VEGF production, thus increasing their angiogenic potential.