12-Lipoxygenase and prostate cancer angiogenesis in the normoxic and hypoxic microenvironment.

摘要

12-lipoxygenase, an arachidonic acid metabolizing enzyme of the lipoxygenase pathway, has been implicated as a major factor in promoting prostate cancer progression and metastasis. The ability of 12-LOX to aggravate the disease was linked to its proangiogenic role. Recent studies have clearly demonstrated that 12-LOX enhances the expression and secretion of the angiogenic factor, vascular endothelial growth factor (VEGF) thus providing a direct link between this enzyme and its angiogenic properties. In the present study we have investigated the relationship between 12-LOX and hypoxia inducible factor-1alpha (HIF-1alpha), a transcription factor involved in the regulation of VEGF expression under hypoxic conditions in solid tumors. Our findings have revealed an interesting aspect of HIF-1alpha regulation by 12-LOX and 12(S)-HETE, which is the modulation of its level and activity under normoxic conditions. The existence and activity of HIF-1alpha under normoxic conditions is an exciting 156 phenomenon and its regulation by 12-LOX adds to the complexity of pathways mediated by this enzyme in promoting prostate cancer angiogenesis and metastasis. We have evidence showing that 12-LOX increases the protein level, mRNA, and functional activity of HIF-1alpha under normoxic conditions, which usually favor the degradation of HIF-1alpha. These findings have strong implications in the identification of mechanisms that stabilize HIF-1alpha in the presence of oxygen triggering downstream pathways which are involved in tumor angiogenesis, survival, and metastasis, thereby enabling us to understand better the pathophysiology of hypoxic tumors.