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    • Human leukemic blasts from both AML and ALL

    2024-05-15

    Human leukemic blasts from both AML and ALL patients demonstrated 5-, 12-, and 15-LOX expression [54]; however, using quantitative PCR, 5-LOX was much more prevalent than 15-LOX. When 15-HETE, 12-HETE, and LTB4 were tested for a direct effect on leukemic blasts, none induced apoptosis [54]. In contrast, the human T-cell leukemia cell line Jurkat was sensitive to 15-HETE and 15-HPETE, showing both enhanced apoptotic markers and reactive oxygen species formation [55]. In an apoptosis-resistant EBV-converted Burkitt's lymphoma cell line, increased expression of 5-LOX was detected [56]. Addition of 5-LOX inhibitors to the cell culture induced apoptosis. Both 5- and 15-HETE counteracted the induction of apoptosis by 5-LOX inhibitors, suggesting that 5-LOX, rather than 15-LOX, may be involved in lymphomagenesis [56]. Biopsies of both non-Hodgkin lymphoma (NHL) and classical Hodgkin lymphoma (HL) were tested for the expression of 15-LOX-1 by immunohistochemistry [57]. No expression was detected in the NHL samples, whereas in 85% of the HL samples the actual Reed–Sternberg cells (tumor cells of classical HL) stained positive [57]. In addition, an HL cell line (L1236) showed mRNA expression of 15-LOX-1. The enzyme was localized at the cytosol, and translocated to the cell membrane upon increase in intracellular calcium levels [57]. The same research group also tested a primary mediastinal B-cell lymphoma (PMBCL) cell line for 15-LOX-1 expression. Untreated cells did not produce 15-HETE after incubation with arachidonic VE-822 australia [58], consistent with lack of 15-LOX-1 protein in PMBCL cell lines and in tumor biopsies, although 15-LOX-1 mRNA was documented by RT-PCR [59]. After treatment with IL-4 (as well as IL-13), both 15-HETE production (in the presence of AA) and 15-LOX-1 expression were detected [58]. These findings were not corroborated in a different PMBCL cell line [58]. Interestingly, the common expression of 15-LOX-1 reiterates the many phenotypic similarities between PMBCL and HL. The role of 15-LOX in multiple myeloma (MM) has not been studied extensively. An early publication reported arachidonic acid incorporation into the membranes of three MM cell lines; however, LTB4, LXA4 and B4, and 12- and 15-HETE had no effect on cell proliferation [60]. In summary, the role of 15-LOX in hematologic malignancies awaits further elucidation.
    Discussion The impact of 15-LOX expression and activity has been studied in various pathological states, including the microvascular complications of diabetes mellitus, obesity, atherosclerosis, hypertension, renal dysfunction, cerebrovascular disease, Alzheimer's disease, and Parkinson's disease [61]. In complex processes, such as the formation of atherosclerotic plaques, evidence points to a dual role for 15-LOX, i.e., both protective against, and promoting, atherogenesis [61]. Similar conflicting evidence points to a protective role against acute and perhaps even chronic kidney injury, alongside a vasoconstrictive and pro-inflammatory effect promoting renal hypertension and vascular injury [61]. Moreover, discussing the role of 15-LOX in mediating inflammation is challenging due to conflicting findings in different inflammatory settings. Whereas in experimental inflammation and fibrosis several studies point to beneficial actions exerted by this enzyme [62–64]. In airway inflammation there is active debate whether 15-LOX exerts an anti-inflammatory effect [65], or a pathological, pro-inflammatory one [66]. Therefore, it is not surprising that opposing findings on the function and significance of 15-LOX in human malignant diseases surface in the current review. Can two isozymes with considerable resemblance be on the one hand devastating in promoting neoplastic transformation and metastasis formation, and on the other protective in keeping cancer at bay? Clearly, it is difficult to come up with a plausible answer to such a conundrum using non-comparable scientific models. For example, the availability and usage of different substrates by 15-LOX is reflected in the net biologic effect. Substrates such as arachidonic acid and DHA are oxygenated by 15-LOX to different degrees. This may lead to the production of different metabolites at varying concentrations with conflicting actions. Metabolism of DHA, an ω-3 polyunsaturated fatty acid from foodstuffs, may lead to the production of protectin D1, or resolvins of the D series [6]. These potent anti-inflammatory mediators dampen deleterious tissue injury in inflammatory settings and thus may hinder tumor growth in the malignant milieu, which is supported by chronic inflammation [67]. Conversely, metabolism of arachidonic acid by eosinophils and mast cells may lead to the production of eoxins, proinflammatory mediators that are structurally related to the cysteinyl-leukotrienes, and enhance vascular permeability [68]. Protectins, resolvins, and eoxins exemplify the myriad of bioactive products generated by 15-LOX in various tissues. At the same token, they represent the wide range of actions exerted by 15-LOX enzymatic activity. This versatility is seldom explored by researchers who focus on the readily produced and abundant metabolites, such as 15-HETE and 13-HODE.