ALOX15 - Knowledge

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and TRansgenic Adenocarcinoma of Mouse Prostate. Targeted overexpression of h15-LO-1 (a gene overexpressed in human PCa and HGPIN) to mouse prostate is sufficient to promote epithelial proliferation and mPIN development. These results support 15-LO-1 as having a role in prostate tumor initiation and as an early target for dietary or other prevention strategies. The FLiMP mouse model should also be useful in crosses with other GEM models to further define the combinations of molecular alterations necessary for PCa progression.

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between their ω-13 and ω-12 carbons, human ALOX15 forms ω-6 peroxy intermediates; in PUFAs that do have this third double bound, human ALOX15 makes the ω-6 peroxy intermediate but also small amounts of the ω-9 peroxy intermediate. Rodent Alox15 enzymes, in contrast, produce almost exclusively ω-9 peroxy intermediates. Concurrently, ALOX15 and rodent Alox15 enzymes rearrange the carbon-carbon double bonds to bring them into the 1

2433: 2372:. While these studies have not yet been shown to translate to human diseases, first and second generation synthetic resolvins and lipoxins, which unlike their natural analogs, are relatively resistant to metabolic inactivation, have been made and tested as inflammation inhibitors in animal models. These synthetic analogs may prove to be clinically useful for treating the cited human inflammatory diseases. 2413:

cancers. Indeed, the ability of docosahexaenoic acid to inhibit the growth of cultured human prostate cancer cells is totally dependent upon the expression of 15-LOX-1 by these cells and appears due to this enzyme's production of docosahexaenoic acid metabolites such as 17(S)-HpETE, 17(S)-HETE, and/or and, possibly, an isomer of protectin DX (10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid)

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resulting from the expression of its mutant forms, regulates ALOX15 promoter activity in human and in mouse, albeit in directionally opposite manners. These studies defined a direct link between ALOX15 gene activity and an established tumor-suppressor gene located in close chromosomal proximity. Kelavkar and Badr (1999) referred to this as evidence that 15-lipoxygenase is a mutator gene. ▼ Mapping

33: 2060:) to a series of products that have been classified as specialized proresolvin mediators. Base on the analogy to docosahexaenoic acid metabolism to resolving D's, it is presumed that a 15-lipoxygenase, most likely ALOX15 in humans, contributes to this metabolism. These products, termed n-3 Resolven D's (RvD 1157:

Kelavkar and Badr (1999) stated that the ALOX15 gene product is implicated in antiinflammation, membrane remodeling, and cancer development/metastasis. Kelavkar and Badr (1999) described experiments yielding data that supported the hypothesis that loss of the TP53 gene, or gain-of-function activities

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By metabolizing ω-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, into lipoxins and resolvins, 15-LOX-1 is thought to be one mechanism by which dietary ω-3 polyunsaturated fatty acids, particularly fish oil, may act to reduce the incidence and/or progression of certain

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gene, is termed ALOX15B, arachidonate 15-lipoxygenase 2, 15-lipoxygenase-2, 15-LOX-2, 15-LO-2, arachidonate 15-lipoxygenase type II, arachidonate 15-lipoxygenase, second type, and arachidonate 15-lipoxygenase; and mouse, rat, and rabbit rodent orthologs of human ALOX15, which share 74-81% amino acid

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Kelavkar et.al have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN), and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM) models of PCa, such as LADY

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In colorectal, breast, and kidney cancers, 15-LOX-1 levels are low or absent compared to the cancers' normal tissue counterparts and/or these levels sharply decline as the cancers progress. These results, as well as a 15-LOX-1 transgene study on colon cancer in mice suggests but do not prove that

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that for the human ALOX15 are located between carbons 10 and 9 and 7 and 6 as numbered counting backward from the last or omega (i.e. ω) carbon at the methyl end of the PUFA (these carbons are also termed ω-10 and ω-9 and ω-7 and ω-6). In PUFAs that do not have a third carbon-carbon double bound

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it produces in rodents; although rodent 12/15-lipoxygenase differs from human ALOX15 in the profile of the PUFA metabolites that it produces as well as various other parameters (e.g. tissue distribution), these genetic studies allow that human ALOX15 and the specialized proresolving mediators it

1540:; one or more of these effects may be at least in part responsible for their ability to promote inflammatory responses, alter the growth of various times of human cancer cell lines, contract various types of blood vessels, and stimulate pathological fibrosis in pulmonary arteries and liver (see 1290:

The distribution of Alox15 in sub-human primates and, in particular, rodents differs significantly from that of human ALOX15; this, along with their different principal product formation (e.g. 12-HETE rather than 15-HETE) has made the findings of Alox15 functions in rat, mouse, or rabbit models

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rather than 15-lipoxygenase activity. Consequently, human ALOX15 is now referred to as arachidonate-15-lipoxygenase-1, 15-lipoxygenase-1, 15-LOX-1, 15-LO-1, human 12/15-lipoxygenase, leukocyte-type arachidonate 12-lipoxygenase, or arachidonate omega-6 lipoxygenase. The second discovered human

1568:) and thereby may serve to signal for the degradation of the mitochondria and the maturation of these precursors to red blood cells in mice. This pathway operates along with two other mitochondria-removing pathways and therefore does not appear essential for mouse red blood cell maturation. 2375:

By metabolizing the ω-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, into 17-HpDHA, 17-HDHA, and the resolvins and protectins, 15-LOX-1's metabolic action is thought to be one mechanism by which dietary ω-3 polyunsaturated fatty acids, particularly

1799:). As at least a partial consequence of these receptor-directed actions, one or both the two ALOX15 products exhibit pro-inflammation, diabetes-inducing, and vasodilation activities in animal models; cancer-promoting activity on cultured human cancer cells; and other actions (see 1586:(LX)A4, LXB4, AT-LXA4, and AT-LXB4; these metabolites are members of the specialized proresolving mediator class of anti-inflammatory agents that contribute to the resolution of inflammatory responses and inflammation-based diseases in animal models and, potentially, humans (see 2290:. These mice also show an accelerated rate of progression of atherosclerosis whereas mice made to overexpress 12/15-lipoxygenase exhibit a delayed rate of atherosclerosis development. Alox15 overexpressing rabbits exhibited reduced tissue destruction and bone loss in a model of 1161:

By PCR analysis of a human-hamster somatic hybrid DNA panel, Funk et al. (1992) demonstrated that genes for 12-lipoxygenase and 15-lipoxygenase are located on human chromosome 17, whereas the most unrelated lipoxygenase (5-lipoxygenase) was mapped to chromosome 10.

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Human ALOX15 was initially named arachidonate 15-lipoxygenase or 15-lipoxygenase but subsequent studies uncovered a second human enzyme with 15-lipoxygenase activity as well as various non-human mammalian Alox15 enzymes that are closely related to and therefore

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James A, Daham K, Backman L, Brunnström A, Tingvall T, Kumlin M, Edenius C, Dahlén SE, Dahlén B, Claesson HE (2013). "The influence of aspirin on release of eoxin C4, leukotriene C4 and 15-HETE, in eosinophilic granulocytes isolated from patients with asthma".

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López-Vicario C, Rius B, Alcaraz-Quiles J, García-Alonso V, Lopategi A, Titos E, Clària J (May 2015). "Pro-resolving mediators produced from EPA and DHA: Overview of the pathways involved and their mechanisms in metabolic syndrome and related liver diseases".

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isomers (e.g. 1S-hydroxy-14S,15S-epoxy-5Z,8Z,12E-eicosatrienoic acid (14,15-HXA3) and 13R-hydroxy-14S,15S-epoxy-5Z,8Z,11Z-eicosatrienoic acid (14,15-HXB3)) which may contribute to the regulation of inflammation responses and

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Mice made deficient in their 12/15-lipoxygenase gene (Alox15) exhibit a prolonged inflammatory response along with various other aspects of a pathologically enhanced inflammatory response in experimental models of

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Kelavkar U, Wang S, Montero A, Murtagh J, Shah K, Badr K (July 1998). "Human 15-lipoxygenase gene promoter: analysis and identification of DNA binding sites for IL-13-induced regulatory factors in monocytes".

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Kroschwald P, Kroschwald A, Kühn H, Ludwig P, Thiele BJ, Höhne M, Schewe T, Rapoport SM (April 1989). "Occurrence of the erythroid cell specific arachidonate 15-lipoxygenase in human reticulocytes".

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Hepoxilin A3 and Hepoxilin B3 along with their respective tri-hydroxyl metabolites, trioxilin A3 and trioxilin B3. These metabolites have been reported to have anti-inflammatory activity, to have

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The PUFA epoxide of arachidonic acid made by ALOX15 - eoxin A4 may also be conjugated with glutathione to form eoxin B4 which product can be further metabolized to eoxin C4, and eoxin D4.

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Veldink GA, Vliegenthart JF, Boldingh J (February 1970). "Proof of the enzymatic formation of 9-hydroperoxy-10-trans, 12-cis-octadecadienoic acid from linoleic acid by soya lipoxygenase".

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intermediate that is attacked by a water molecule to form epoxy-hydrpoxy PUFA products. Eoxins stimulate vascular permeability in an ex vivo human vascular endothelial model system.

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Kratky D, Lass A, Abuja PM, Esterbauer H, Kühn H (January 1999). "A sensitive chemiluminescence method to measure the lipoxygenase catalyzed oxygenation of complex substrates".

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of ALOX15, termed Alox15, are widely distributed in animal and plant species but commonly have different enzyme activities and make somewhat different products than ALOX15.

4985:"Effects of mutant p53 expression on human 15-lipoxygenase-promoter activity and murine 12/15-lipoxygenase gene expression: evidence that 15-lipoxygenase is a mutator gene" 4317:"Effects of mutant p53 expression on human 15-lipoxygenase-promoter activity and murine 12/15-lipoxygenase gene expression: evidence that 15-lipoxygenase is a mutator gene" 4256:"Effects of mutant p53 expression on human 15-lipoxygenase-promoter activity and murine 12/15-lipoxygenase gene expression: evidence that 15-lipoxygenase is a mutator gene" 1165:

Kelavkar and Badr (1999) stated that the ALOX15 gene maps to 17p13.3 in close proximity to the tumor-suppressor gene TP53 (191170). In humans, it is encoded by the ALOX15

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Sigal E, Dicharry S, Highland E, Finkbeiner WE (April 1992). "Cloning of human airway 15-lipoxygenase: identity to the reticulocyte enzyme and expression in epithelium".

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Kritzik MR, Ziober AF, Dicharry S, Conrad DJ, Sigal E (June 1997). "Characterization and sequence of an additional 15-lipoxygenase transcript and of the human gene".

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Lei ZM, Rao CV (February 1992). "The expression of 15-lipoxygenase gene and the presence of functional enzyme in cytoplasm and nuclei of pregnancy human myometria".

2294:. Finally, Control mice, but not 12/15-lipoxygense deficient mice responded to eicospentaenoic acid administration by decreasing the number of lesions in a model of 1424:. The human enzyme is particularly active on linoleic acid, preferring it over arachidonic acid. It is less active on PUFA that are esters within the cited lipids. 1223:

Both human ALOX15 and ALOX15B genes are located on chromosome 17; their product proteins have an amino acid sequence identity of only ~38%; they also differ in the

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Sigal E, Craik CS, Highland E, Grunberger D, Costello LL, Dixon RA, Nadel JA (December 1988). "Molecular cloning and primary structure of human 15-lipoxygenase".

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where they may be stored and subsequently released during cell stimulation. As one aspect of this processing, the two products are progressively esterified in

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Shureiqi I, Wu Y, Chen D, Yang XL, Guan B, Morris JS, Yang P, Newman RA, Broaddus R, Hamilton SR, Lynch P, Levin B, Fischer SM, Lippman SM (December 2005).

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Jiang WG, Watkins G, Douglas-Jones A, Mansel RE (April 2006). "Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer".

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Claesson HE (September 2009). "On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma".

1533: 4749:"Arachidonate 15-lipoxygenase (omega-6 lipoxygenase) from human leukocytes. Purification and structural homology to other mammalian lipoxygenases" 2392:

metabolites have been suggested as potential contributors to, and therefore targets for the future study and treatment of, human allergen-induced

2081: 3348:"The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant?" 2174: 2607: 2024: 1930:

Ds (RvDs), i.e. RvD-1, RvD2, RvD3, RvD4, RvD5, RvD6, and protectin Ds (PDs), i.e. PD1, PDX, 20-hydroxy-PD1, 17-epi-PD1, and 10-epi-PD1 (see

1920: 1541: 3240:"15-Lipoxygenase-1-mediated metabolism of docosahexaenoic acid is required for syndecan-1 signaling and apoptosis in prostate cancer cells" 2939:"15-Lipoxygenase-1-mediated metabolism of docosahexaenoic acid is required for syndecan-1 signaling and apoptosis in prostate cancer cells" 2589: 4848:"Membrane translocation of 15-lipoxygenase in hematopoietic cells is calcium-dependent and activates the oxygenase activity of the enzyme" 3576:"Identification and profiling of targeted oxidized linoleic acid metabolites in rat plasma by quadrupole time-of-flight mass spectrometry" 1811:

activity, to promote pain perception, to reverse oxidative stress in cells, and to promote insulin secretion in animal model systems (see

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Izumi T, Rådmark O, Samuelsson B (1991). "Purification of 15-lipoxygenase from human leukocytes, evidence for the presence of isozymes".

4209:"Conditional expression of human 15-lipoxygenase-1 in mouse prostate induces prostatic intraepithelial neoplasia: the FLiMP mouse model" 3037:"Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells" 1834:

1 (BLT1). This allows the possibility that 12-oxo-ETE contributes to the pro-inflammatory and other activities that BLT2 regulates (see

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Sigal E, Nadel JA (December 1988). "Arachidonic acid 15-lipoxygenase and airway epithelium. Biologic effects and enzyme purification".

3449:"Metabolism of polyunsaturated fatty acids by skin epidermal enzymes: generation of antiinflammatory and antiproliferative metabolites" 2146: 2316:À huge and growing number of studies in animal models suggest that 15-LOX-1 and its lipoxin, resolvin, and protectin metabolites (see 1087: 1080: 5084: 4117:

Zuo X, Peng Z, Wu Y, Moussalli MJ, Yang XL, Wang Y, Parker-Thornburg J, Morris JS, Broaddus RR, Fischer SM, Shureiqi I (May 2012).

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Romano M, Cianci E, Simiele F, Recchiuti A (August 2015). "Lipoxins and aspirin-triggered lipoxins in resolution of inflammation".

3096:"Positional specificity of a reticulocyte lipoxygenase. Conversion of arachidonic acid to 15-S-hydroperoxy-eicosatetraenoic acid" 1612: 1763:)-HETE, possess a broad range of activities. One or both of these compounds stimulates cells by binding with and activating two 5217: 5560: 1736: 604:

oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen

5050: 2572: 2121:)-HpODE, non-human 15-LOX1 orthologs such as mouse 12/15-LOX and soybean 15-LOX metabolize linoleic acid to 9-hydroperoxy-10 2093:

Human 15-LOX-1 prefers linoleic acid over arachidonic acid as its primary substrate, oxygenating it at carbon 13 to form 13(

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receptors to stimulate a variety of responses related to monocyte maturation, lipid metabolism, and neuron activation (see

2158: 5178: 2551: 4921:"Induction of 15-lipoxygenase expression by IL-13 requires tyrosine phosphorylation of Jak2 and Tyk2 in human monocytes" 4572:

Sloane DL, Leung R, Craik CS, Sigal E (November 1991). "A primary determinant for lipoxygenase positional specificity".

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Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, Lindbom L, Björkholm M, Claesson HE (2008).

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The 2015 version of this article was updated by an external expert under a dual publication model. The corresponding

1915:-HDHA). One or both of these products stimulate human breast and prostate cell lines to proliferate in culture and 17 4078:"Human 5-, 12- and 15-lipoxygenase-1 coexist in kidney but show opposite trends and their balance changes in cancer" 242: 2885:"The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis" 2576: 2555: 2528: 1517: 1509: 17: 2298:. These studies indicate that the suppression of inflammation is a major function of 12/15-lipoxygenase and the 4619:"Immunocytochemical localization of arachidonate 15-lipoxygenase in erythrocytes, leukocytes, and airway cells" 2523: 2114: 2019:, in cells, and may thereby serve an anti-inflammatory function. These products may be further metabolized to: 925: 3346:

Ramon S, Baker SF, Sahler JM, Kim N, Feldsott EA, Serhan CN, Martínez-Sobrido L, Topham DJ, Phipps RP (2014).

5415: 5168: 3181:"15-lipoxygenase metabolites of docosahexaenoic acid inhibit prostate cancer cell proliferation and survival" 2138: 1368:

Human ALOX15 can also convert the peroxy PUFA intermediate to a cyclic ether with a three-atom ring, i.e. an

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protein composed of 662 amino acids. 15-LO is to be distinguished from another human 15-lipoxygenase enzyme,

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Kelavkar U, Glasgow W, Eling TE (June 2002). "The effect of 15-lipoxygenase-1 expression on cancer cells".

1607:(e.g. eoxin C4, 14,15-eoxin D4, and eoxin E4) which have pro-inflammatory actions and contribute to severe 1448:

configuration). ALOX15 adds a hydroperoxy residue to AA at carbons 15 and to a lesser extent 12 to form 15(

81: 4037:"Mechanisms of aspirin-intolerant asthma: identifying inflammatory pathways in the pathogenesis of asthma" 1227:

that they prefer as substrates and exhibit different product profiles when acting on the same substrates.

5183: 5139: 5125: 3490:"Evidence for a dominant role of lipoxygenase(s) in the oxidation of LDL by mouse peritoneal macrophages" 1325: 1220:

identity with the human enzyme, are commonly termed Alox15, 12/15-lipoxygenase, 12/15-LOX, or 12/15-LO).

278: 177: 5530: 1764: 1224: 1151: 271: 170: 2218: 5516: 5503: 5490: 5477: 5464: 5451: 5438: 5400: 5153: 1839: 1827: 1772: 1529: 1500:)-HpETE in a product ratio of ~4-9 to 1. Both products may be rapidly reduced by ubiquitous cellular 3574:

Yuan ZX, Rapoport SI, Soldin SJ, Remaley AT, Taha AY, Kellom M, Gu J, Sampson M, Ramsden CE (2013).

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of human ALOX15. Many of the latter Alox15 enzymes nonetheless possess predominantly or exclusively

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Gohara A, Eltaki N, Sabry D, Murtagh D, Jankun J, Selman SH, Skrzypczak-Jankun E (October 2012).

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O'Flaherty JT, Wooten RE, Samuel MP, Thomas MJ, Levine EA, Case LD, Akman SA, Edwards IJ (2013).

1831: 1537: 1437: 1142:(also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other 1063: 1042: 1016: 995: 2369: 2202: 1501: 3895:"The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution" 3674:"The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution" 5333: 5252: 2441: 1401: 1248: 153: 37: 5062: 109: 5405: 5173: 5163: 4996: 4581: 4482: 4471:"Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase" 4328: 4267: 3300: 3192: 3179:

O'Flaherty JT, Hu Y, Wooten RE, Horita DA, Samuel MP, Thomas MJ, Sun H, Edwards IJ (2012).

3048: 2764: 2641: 1784: 1659: 1405: 1397: 1393: 1244: 3944:"Proresolving actions of a new resolvin D1 analog mimetic qualifies as an immunoresolvent" 1803:). The two products are also further metabolized to various bioactive products including: 1154:

to a wide range of physiologically and pathologically important products. ▼ Gene Function

8: 5575: 5369: 5056: 3812: 2823: 1780: 5000: 4585: 4486: 4332: 4271: 4119:"Effects of gut-targeted 15-LOX-1 transgene expression on colonic tumorigenesis in mice" 3304: 3196: 3137:"Hydroxyeicosanoids bind to and activate the low affinity leukotriene B4 receptor, BLT2" 3052: 2768: 2645: 5302: 5226: 5188: 4907: 4605: 4452: 4435: 4393: 4233: 4208: 4143: 4118: 4017: 3968: 3943: 3919: 3894: 3870: 3845: 3821: 3800: 3698: 3673: 3654: 3600: 3575: 3421: 3396: 3372: 3347: 3323: 3288: 3264: 3239: 3215: 3180: 3071: 3036: 3012: 2987: 2963: 2938: 2909: 2884: 2728: 2703: 2489: 2454: 2365: 2357: 1421: 113: 4967: 4830: 4800: 4783: 4765: 4748: 4731: 4643: 4618: 3506: 3489: 3112: 3095: 2664: 2629: 2380:, act to ameliorate inflammation, inflammation-related diseases, and certain cancers. 795: 790: 785: 780: 775: 770: 765: 760: 755: 750: 745: 740: 735: 730: 725: 720: 715: 710: 705: 700: 695: 690: 685: 680: 675: 659: 654: 649: 644: 639: 634: 618: 613: 608: 603: 598: 593: 588: 583: 578: 573: 568: 563: 558: 5024: 5019: 4984: 4971: 4942: 4899: 4869: 4834: 4805: 4770: 4735: 4706: 4677: 4673: 4648: 4597: 4560: 4539: 4510: 4505: 4470: 4457: 4422: 4385: 4356: 4351: 4316: 4295: 4290: 4255: 4238: 4189: 4148: 4099: 4058: 4009: 3973: 3924: 3875: 3826: 3781: 3746: 3703: 3646: 3605: 3556: 3542: 3511: 3470: 3426: 3377: 3328: 3269: 3220: 3158: 3117: 3076: 3017: 2968: 2914: 2862: 2827: 2792: 2787: 2752: 2733: 2669: 2494: 2476: 2057: 2023:

Resolvin E3, a specialized proresolvin mediator with anti-inflammatory activity (see

1938:). These products are members of, and have a wide range of activities common to, the 1931: 1350: 1280: 1276: 61: 4911: 4702: 4418: 4397: 4021: 3658: 1801:

12-Hydroxyeicosatetraenoic acid § Activities and possible clinical significance

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between carbons 5-6, 8-9, 11-12, and 14-15; these double bonds are in the cis (see

358: 289: 233: 188: 2900: 2704:"Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15)" 2455:"Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15)" 93: 5395: 5379: 5292: 4846:

Brinckmann R, Schnurr K, Heydeck D, Rosenbach T, Kolde G, Kühn H (January 1998).

4436:"Purification of two forms of arachidonate 15-lipoxygenase from human leukocytes" 3777: 3742: 3313: 3205: 3003: 2349: 2345: 2206: 2170: 1256: 1211: 333: 117: 3641: 3624: 2858: 2612:

National Center for Biotechnology Information, U.S. National Library of Medicine

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National Center for Biotechnology Information, U.S. National Library of Medicine

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for and possible contributors to the inflammatory component of atherosclerosis,

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Specialized proresolving mediators § DHA-derived protectins/neuroprotectins

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12-Hydroxyeicosatetraenoic acid § Receptor targets and mechanisms of action

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