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  • Fig summarizes the oxidative metabolism of arachidonic acid

    2023-01-18

    Fig. 1 summarizes the oxidative metabolism of arachidonic XEN445 by lipoxygenases cyclooxygenases and cytochrome P450. Lipoxygenases in humans are expressed in a tissue-specific fashion: 5-LOX is mainly expressed in leukocytes, 12-LOX in platelets, and 15-LOX-1 in reticulocytes, eosinophils, and macrophages. In mice, the analogous enzyme to the human 15-LOXs is 12/15-LOX, an enzyme biased toward the production of oxygenated products with a hydroxyl group on carbon 12 in arachidonic acid and carbon 14 in DHA, rather than carbon 15 and 17, respectively. In the 1990s, an additional 15-LOX isozyme, 15-LOX-2, was reported. Hence, publications through 1997 preceded the distinction between the two 15-LOXs and results from these studies are limited in their interpretation. 15-LOX-2 is expressed in skin, cornea, prostate, lung, and esophagus [2,3]. It shares a 35% identity in amino acids with 15-LOX-1, and is more restricted to 15-carbon oxygenation and to arachidonic acid as substrate than 15-LOX-1 [4]. The latter can also metabolize linoleic acid, thus forming 13-hydroxyoctadecadienoic acid (13-HODE). Fig. 2 summarizes the oxidative metabolism of linoleic acid and other polyunsaturated acids (PUFA) by lipoxygenases. In addition, the main differences between the two 15-LOXs are briefly reviewed in Table 1. The metabolic products of LOXs are diverse. 5-LOX oxygenates arachidonic acid to 5-HPETE, which is further metabolized by 5-LOX to the unstable leukotriene (LT) A4. This LT is transformed in part to the proinflammatory leukotrienes LTB4, LTC4, LTD4, and LTE4. 5-HPETE may also undergo reduction to 5-HETE, and both 5-HETE and LTB4 have been reported to recruit and activate inflammatory cells, as well as to increase vascular permeability, both key steps in tumorigenesis [5]. LTA4 released from leukocytes may also be transformed by platelet 12-LOX or mucosal 15-LOX to lipoxin (LX) A4 and B4. Lipoxins counter-regulate the main aspects of inflammation as well as halt the recruitment of inflammatory cells [6]. Opposing actions were reported for both 15-LOX-1 [7] and 15-LOX-2 [5] in carcinogenesis. This dispute extends to both solid tumors and hematological malignancies. The following sections will review evidence that supports either a pro-carcinogenic role or a tumor-suppressor effect for metabolites of the different 15-LOXs in various types of neoplasms.
    Prostate cancer The interest in 15-LOX in prostate cancer (PCa) has spanned more than a decade and a half. Spindler et al. [8] first suggested a carcinogenic role for 15-LOX-1 metabolites by detecting high levels of 13-HODE, a linoleic acid derivative, in both human PC specimens and PCa cell lines. Concomitantly, the presence of indeterminate 15-LOX was documented in these cell lines. When athymic nude mice were injected with PCa cell lines overexpressing 15-LOX-1, much larger prostatic tumors were generated as compared to those injected with PC cell lines with normal expression of 15-LOX-1 [9]. Following the discovery of 15-LOX-2 and its expression in prostate tissue, the development of a specific antibody directed against this isozyme allowed its detection in prostatic hyperplasia, whereas in PCa cells its levels were reduced [10]. This paved the way for the tumor-suppressor paradigm for 15-LOX-2 in PCa, later substantiated by evidence that its metabolite, 15-HETE, activates peroxisome proliferator-activated receptor gamma (PPARγ) and inhibits the proliferation of PCa cell lines [11]. The contrasting roles of 15-LOX-1 as an oncogene and 15-LOX-2 as a tumor-suppressor were supported by opposing effects of their products on mitogen-activated protein kinase (MAPK) signaling: 13-HODE up-regulates MAPK activity, thus enhancing PPARγ phosphorylation and subsequently decreasing PPARγ transcriptional activity, whereas 15-HETE down-regulates MAPK activity with a stimulatory effect on PPARγ activity [12]. The Akt kinase is another signaling molecule that is affected by 13-HODE and 15-HETE in opposing manners, although to a lesser degree than MAPK. Hence, the effect of synthetic 15-LOX metabolites on MAPK signaling was demonstrated at lower, more physiologically relevant concentrations. Activation of the insulin growth factor-1 receptor (IGF-1R) promoter and IGF-1 binding were also promoted by 13-HODE [13]. IGF-1-stimulated MAPK and Akt activation was also increased by 15-LOX-1 overexpression, and blocking of 15-LOX-1 activity inhibited the proliferation of PCa cells, thus supporting a pro-tumorigenic role for 15-LOX-1 metabolites [13].