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Emerging cellular functions of the lipid metabolizing enzyme 15-Lipoxygenase-1.

ABSTRACT: The oxygenation of polyunsaturated fatty acids such as arachidonic and linoleic acid through lipoxygenases (LOXs) and cyclooxygenases (COXs) leads to the production of bioactive lipids that are important both in the induction of acute inflammation and its resolution. Amongst the several isoforms of LOX that are expressed in mammals, 15-LOX-1 was shown to be important both in the context of inflammation, being expressed in cells of the immune system, and in epithelial cells where the enzyme has been shown to crosstalk with a number of important signalling pathways. This review looks into the latest developments in understanding the role of 15-LOX-1 in different disease states with emphasis on the emerging role of the enzyme in the tumour microenvironment as well as a newly re-discovered form of cell death called ferroptosis. We also discuss future perspectives on the feasibility of use of this protein as a target for therapeutic interventions.

SUBMITTER: Colakoglu M

PROVIDER: S-EPMC6528901 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Emerging cellular functions of the lipid metabolizing enzyme 15-Lipoxygenase-1.

Çolakoğlu Melis M Tunçer Sinem S Banerjee Sreeparna S

Cell proliferation 20180730 5

The oxygenation of polyunsaturated fatty acids such as arachidonic and linoleic acid through lipoxygenases (LOXs) and cyclooxygenases (COXs) leads to the production of bioactive lipids that are important both in the induction of acute inflammation and its resolution. Amongst the several isoforms of LOX that are expressed in mammals, 15-LOX-1 was shown to be important both in the context of inflammation, being expressed in cells of the immune system, and in epithelial cells where the enzyme has b ...[more]

PMID: 30062726

Similar Datasets

Arachidonate 15-lipoxygenase enzyme products increase platelet aggregation and thrombin generation.

Project description:Atherosclerotic cardiovascular diseases are the leading causes of morbidity and mortality worldwide. We have previously shown that arachidonate 15-lipoxygenase B (ALOX15B) is highly expressed in atherosclerotic carotid plaques, and elucidation of mechanisms downstream of activated lipoxygenases may be relevant to our understanding of the genesis of atherosclerotic diseases. We examined 120 carotid plaques from patients with symptomatic carotid artery stenosis and showed that the extent of ALOX15B staining was significantly increased in carotid plaques with thrombosis. Impedance aggregometry analyses showed that the ALOX15B enzyme products 15-HETE and 15-HPETE increased platelet aggregation. By using a calibrated automatic thrombin assay, we showed that the ALOX15B products also increased both peak levels of thrombin and the total endogenous thrombin potential. Moreover, platelet aggregation was increased by addition of cell lysates from ischemic human macrophages, whereas platelet aggregation was reduced after knockdown of ALOX15B in human macrophages. Our data show that ALOX15B expression in human carotid plaques is associated with thrombus formation and that enzyme products of ALOX15B increase platelet aggregation and thrombin generation. We therefore propose that activated ALOX15B in macrophages may play a role in the induction of atherothrombotic events by increasing platelet aggregation and thrombin generation.

| S-EPMC3922896 | biostudies-literature

Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer.

Project description:15-Lipoxygenase-2 (15-LOX2) is a human-specific lipid-peroxidizing enzyme most prominently expressed in epithelial cells of normal human prostate but downregulated or completely lost in>70% of prostate cancer (PCa) cases. Transgenic expression of 15-LOX2 in the mouse prostate surprisingly causes hyperplasia. Here we first provide evidence that 15-LOX2-induced prostatic hyperplasia does not progress to PCa even in p53(+/-) or p53(-/-) background. More important, by generating 15-LOX2; Hi-Myc double transgenic (dTg) mice, we show that 15-LOX2 expression inhibits Myc-induced PCa development, such that in the 3-month- and 6-month-old dTg mice, there is a significant reduction in prostate intraneoplasia (PIN) and PCa prevalent in age-matched Hi-Myc prostates. The dTg prostates show increased cell senescence and expression of several senescence-associated molecules, including p27, phosphorylated Rb, and Rb1cc1. We further show that in HPCa, 15-LOX2 and c-Myc manifest reciprocal protein expression patterns. Moreover, RB1CC1 accumulates in senescing normal human prostate (NHP) cells, and in both NHP and RWPE-1 cells, the 15-LOX2 metabolic products 15(S)-HPETE and 15(S)-HETE induce RB1CC1. We finally show that unlike 15-LOX2, RB1CC1 is not lost but rather frequently overexpressed in PCa samples. RB1CC1 knockdown in PC3 cells enhances clonal growth in vitro and tumor growth in vivo. Together, our present studies provide evidence for tumor-suppressive functions for both 15-LOX2 and RB1CC1.

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12/15-Lipoxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function.

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Macrophage 12/15 lipoxygenase expression increases plasma and hepatic lipid levels and exacerbates atherosclerosis.

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Loss of 15-lipoxygenase disrupts T<sub>reg</sub> differentiation altering their pro-resolving functions.

Project description:Regulatory T-cells (Tregs) are central in the maintenance of homeostasis and resolution of inflammation. However, the mechanisms that govern their differentiation and function are not completely understood. Herein, we demonstrate a central role for the lipid mediator biosynthetic enzyme 15-lipoxygenase (ALOX15) in regulating key aspects of Treg biology. Pharmacological inhibition or genetic deletion of ALOX15 in Tregs decreased FOXP3 expression, altered Treg transcriptional profile and shifted their metabolism. This was linked with an impaired ability of Alox15-deficient cells to exert their pro-resolving actions, including a decrease in their ability to upregulate macrophage efferocytosis and a downregulation of interferon gamma expression in Th1 cells. Incubation of Tregs with the ALOX15-derived specilized pro-resolving mediators (SPM)s Resolvin (Rv)D3 and RvD5n-3 DPA rescued FOXP3 expression in cells where ALOX15 activity was inhibited. In vivo, deletion of Alox15 led to increased vascular lipid load and expansion of Th1 cells in mice fed western diet, a phenomenon that was reversed when Alox15-deficient mice were reconstituted with wild type Tregs. Taken together these findings demonstrate a central role of pro-resolving lipid mediators in governing the differentiation of naive T-cells to Tregs.

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15-Lipoxygenase-1 biosynthesis of 7S,14S-diHDHA implicates 15-lipoxygenase-2 in biosynthesis of resolvin D5.

Project description:The two oxylipins 7S,14S-dihydroxydocosahexaenoic acid (diHDHA) and 7S,17S-diHDHA [resolvin D5 (RvD5)] have been found in macrophages and infectious inflammatory exudates and are believed to function as specialized pro-resolving mediators (SPMs). Their biosynthesis is thought to proceed through sequential oxidations of DHA by lipoxygenase (LOX) enzymes, specifically, by human 5-LOX (h5-LOX) first to 7(S)-hydroxy-4Z,8E,10Z,13Z,16Z,19Z-DHA (7S-HDHA), followed by human platelet 12-LOX (h12-LOX) to form 7(S),14(S)-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-DHA (7S,14S-diHDHA) or human reticulocyte 15-LOX-1 (h15-LOX-1) to form RvD5. In this work, we determined that oxidation of 7(S)-hydroperoxy-4Z,8E,10Z,13Z,16Z,19Z-DHA to 7S,14S-diHDHA is performed with similar kinetics by either h12-LOX or h15-LOX-1. The oxidation at C14 of DHA by h12-LOX was expected, but the noncanonical reaction of h15-LOX-1 to make over 80% 7S,14S-diHDHA was larger than expected. Results of computer modeling suggested that the alcohol on C7 of 7S-HDHA hydrogen bonds with the backbone carbonyl of Ile399, forcing the hydrogen abstraction from C12 to oxygenate on C14 but not C17. This result raised questions regarding the synthesis of RvD5. Strikingly, we found that h15-LOX-2 oxygenates 7S-HDHA almost exclusively at C17, forming RvD5 with faster kinetics than does h15-LOX-1. The presence of h15-LOX-2 in neutrophils and macrophages suggests that it may have a greater role in biosynthesizing SPMs than previously thought. We also determined that the reactions of h5-LOX with 14(S)-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-DHA and 17(S)-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-DHA are kinetically slow compared with DHA, suggesting that these reactions may be minor biosynthetic routes in vivo. Additionally, we show that 7S,14S-diHDHA and RvD5 have anti-aggregation properties with platelets at low micromolar potencies, which could directly regulate clot resolution.

| S-EPMC7328043 | biostudies-literature

Gene expression analysis of 15-Lipoxygenase 2 (15-LOX2) transgenic mice

Project description:15-Lipoxygenase 2 (15-LOX2), a human-specific lipid-peroxidizing enzyme, is mainly expressed in luminal compartment of the normal prostate and often decreased or lost in prostate cancer (PCa). Previous studies from our lab implicate 15-LOX2 as a functional tumor suppressor. To better understand the biological role of 15-LOX2 in vivo, we established prostate-specific 15-LOX2 transgenic mice using the ARR2PB promoter. Unexpectedly, 15-LOX2 expression resulted in age-dependent prostatic hyperplasia. Interestingly, transgenic expression of 15-LOX2sv-b, a splice variant that lacks the arachidonic acid metabolizing activity, also induced hyperplasia and enlargement of the prostate. Prostatic hyperplasia induced by both 15-LOX2 and 15-LOX2sv-b was associated with an increase in proliferative (i..e., Ki67+) and luminal cells but 15-LOX2-induced hyperplasia was also accompanied by a prominent increase in basal cells. Microarray analysis revealed distinct gene expression profiles that could help explain the prostate phenotypes. Strikingly, 15-LOX2 (but not 15-LOX2sv-b) transgenic prostate showed up-regulation of several well-known stem/progenitor cell molecules including Sca-1, Trop2, p63 and Psca. Prostatic hyperplasia caused by both 15-LOX2 and 15-LOX2sv-b did not progress to PCa over >5 years of observations. Mechanistically, hyperplastic prostate lobes (especially those of the 15-LOX2 mice) showed a dramatic increase in senescent cells revealed by increased SA-ßgal, HP1, and p27Kip1 staining. Collectively, our results suggest that 15-LOX2 expression in mouse prostate leads to hyperplasia that activates the senescence checkpoint, which may in turn function as a barrier to tumor development.

2010-12-16 | GSE15827 | GEO

The Arachidonate 15-Lipoxygenase Enzyme Product 15-HETE Is Present in Heart Tissue from Patients with Ischemic Heart Disease and Enhances Clot Formation.

Project description:Ischemic heart disease is a major cause of death and morbidity and the search for novel therapeutic targets is still required. We have previously shown that the enzyme arachidonate 15 lipoxygenase (ALOX15), which catalyzes the conversion of arachidonic acid to 15-hydroxy eicosatetraenoic acid (15-HETE), is highly expressed in ischemic heart tissue, but its role in the pathogenesis of ischemic heart disease is unclear. Here we showed that expression of ALOX15, but not ALOX12 or ALOX15B, was increased in ischemic versus non-ischemic human heart biopsy samples. A similar ALOX expression pattern was found in hypoxic human cardiomyocytes and cardiac endothelial cells. We also showed that levels of 15-HETE were significantly higher in ischemic versus non-ischemic human heart biopsy samples and showed a tendency to increase in serum from the patients with ischemic heart disease. Moreover, hypoxia increased the production of 15-HETE levels from human cardiomyocytes and cardiac endothelial cells. The hypoxia-induced increase in 15-HETE levels from human cardiomyocytes was inhibited by the ALOX15 inhibitor baicalein. Finally, by using intrinsic rotational thromboelastometry, we showed that human whole blood clotted faster in the presence of 15-HETE. In summary, we propose that increased ALOX15 expression in heart tissue under ischemic conditions may lead to increased production of 15-HETE, potentially contributing to thrombosis.

| S-EPMC4994938 | biostudies-literature

12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases.

Project description:Protein tyrosine phosphatases (PTPs) are regulated through reversible oxidation of the active-site cysteine. Previous studies have implied soluble reactive oxygen species (ROS), like H(2)O(2), as the mediators of PTP oxidation. The potential role(s) of peroxidized lipids in PTP oxidation have not been described. This study demonstrates that increases in cellular lipid peroxides, induced by disruption of glutathione peroxidase 4, induce cellular PTP oxidation and reduce the activity of PDGF receptor targeting PTPs. These effects were accompanied by site-selective increased PDGF beta-receptor phosphorylation, sensitive to 12/15-lipoxygenase (12/15-LOX) inhibitors, and increased PDGF-induced cytoskeletal rearrangements. Importantly, the 12/15-LOX-derived 15-OOH-eicosatetraenoic acid lipid peroxide was much more effective than H(2)O(2) in induction of in vitro PTP oxidation. Our study thus establishes that lipid peroxides are previously unrecognized inducers of oxidation of PTPs. This identifies a pathway for control of receptor tyrosine kinase signaling, which might also be involved in the etiology of diseases associated with increased lipid peroxidation.

| S-EPMC2936618 | biostudies-literature

Activity-Based Probes for 15-Lipoxygenase-1.

Project description:Human 15-lipoxygenase-1 (15-LOX-1) plays an important role in several inflammatory lung diseases, such as asthma, COPD, and chronic bronchitis, as well as various CNS diseases, such as Alzheimer's disease, Parkinson's disease, and stroke. Activity-based probes of 15-LOX-1 are required to explore the role of this enzyme further and to enable drug discovery. In this study, we developed a 15-LOX-1 activity-based probe for the efficient activity-based labeling of recombinant 15-LOX-1. 15-LOX-1-dependent labeling in cell lysates and tissue samples was also possible. To mimic the natural substrate of the enzyme, we designed activity-based probes that covalently bind to the active enzyme and include a terminal alkene as a chemical reporter for the bioorthogonal linkage of a detectable functionality through an oxidative Heck reaction. The activity-based labeling of 15-LOX-1 should enable the investigation and identification of this enzyme in complex biological samples, thus opening up completely new opportunities for drug discovery.

| S-EPMC5218545 | biostudies-literature

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