THE ROLE OF 15-LIPOXYGENASE-1- AND

It is a generally accepted paradigm that there is a direct link between inflammation and tumor progression. During inflammation, there is increased formation of lipid hydroperoxides, mediated either non-enzymatically by reactive oxygen species or enzymatically by lipoxygenases (LOs) or cyclooxygenases (COXs). Lipid hydroperoxides undergo further oxidation into oxo-eicosatetraenoic acids (oxo-ETEs), which are produced and released by cells including macrophages and epithelial cells. Therefore, these oxo-ETEs could potentially mediate biological effects in an autocrine and/or a paracrine manner. In addition, oxo-ETEs conjugate intracellular glutathione (GSH) to form adducts which could serve as biomarkers of oxo-ETE formation. In this study, a targeted lipidomics approach combined with stable isotope dilution methodology was employed to identify and quantify lipid hydroperoxides and their metabolites formed in 15-LO-expressing mouse macrophage cell line (R15L cells) and COX-2 expressing cell models (RIES cells and Caco-2 cells) as well as in mouse hematocytes and primary human monocytes. 15-Oxo-5,8,11,13-(Z,Z,Z,E)-ETE (15-oxo-ETE) was identified and characterized as a major eicosanoid produced in both mouse and human macrophage 15-LO pathway. 15-Oxo-ETE was shown to be a metabolite of arachidonic acid (AA)-derived 15(S)