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15-Lipoxygenases in cancer: A double-edged sword?

https://doi.org/10.1016/j.prostaglandins.2013.07.006Get rights and content

Highlights

  • 15-Lipoxygenase is involved in many cancer-related processes.

  • 15-Lipoxygenase may act as a carcinogen or a tumor suppressor.

  • In some neoplasms, e.g., prostate cancer, this diversity is explained through opposing effects of two 15-lipoxygenase isoenzymes.

  • In colorectal cancer, harnessing 15-lipoxygenase may be therapeutic.

  • The dichotomy in 15-lipoxygenase actions might stem from opposing actions of mono- and di/tri-hydroxy products.

Abstract

Among the lipoxygenases, a diverse family of fatty acid dioxygenases with varying tissue-specific expression, 15-lipoxygenase (15-LOX) was found to be involved in many aspects of human cancer, such as angiogenesis, chronic inflammation, metastasis formation, and direct and indirect tumor suppression. Herein, evidence for the expression and action of 15-LOX and its orthologs in various neoplasms, including solid tumors and hematologic malignancies, is reviewed. The debate surrounding the impact of 15-LOX as either a tumor-promoting or a tumor-suppressing enzyme is highlighted and discussed in the context of its role in other biological systems.

Introduction

The lipoxygenase (LOX) superfamily is abundant in plants, fungi, and animals, and catalyzes the formation of a single specific hydroperoxide derivative from polyunsaturated fatty acids [1]. The nomenclature of LOXs is based on the substrate carbon where oxygenation is catalyzed, and largely the chain length of common substrates determines the specificity of the enzyme. Whereas in plants 18-carbon fatty acids (such as linoleate and linolenate) are the dominant LOX substrates, in animals arachidonate (20-carbon fatty acid) is more common, corresponding to plant 13-LOX and animal 15-LOXs, respectively. Mammalian LOXs oxygenate arachidonic acid to hydroperoxyeicosatetraenoic acids (HPETEs) that are subsequently reduced to their corresponding hydroxyeicosatetraenoic acids (HETEs).

Fig. 1 summarizes the oxidative metabolism of arachidonic acid 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.

Section snippets

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

Renal cell carcinoma

Lipoxygenase involvement in renal cell carcinoma (RCC) development has been scarcely probed. There is one report on macrophages in the renal tumor microenvironment which show an upregulated expression of 15-LOX-2, but not 15-LOX-1, and enhanced production of 15-HETE. Pharmacologic inhibition of LOX promoted the production of CCL2 and IL-10 by these tumor-associated macrophages, suggesting 15-LOX-2 supports immune evasion by tumor cells [17]. Notably, tumor cells were obtained from newly

Lung cancer

A lung carcinoma cell line was demonstrated by Brinckmann and Kuhn [19] to express an indeterminate 15-LOX after culturing with interleukin 4 (IL-4), a type 2 cytokine that exerts a similar effect on human monocytes/macrophages [20]. Detectable mRNA levels of both indeterminate 15-LOX in non-small lung carcinoma (NSCLC) cell lines were also reported by Moody et al. in the absence of IL-4 [21]. Along these lines, nordihydroguaiaretic acid (NDGA), a nonspecific LOX inhibitor, inhibited NSCLC cell

Colorectal carcinoma

The growth rate of murine colon adenocarcinoma tumors decreased upon inhibition of 5-LOX, an enzyme that harbors counteracting properties to 15-LOX [28]. It is not clear whether 15-LOX was associated with this phenomenon, but its expression is induced in the colon carcinoma cell line HTB 38 following treatment with IL-4 [19]. Expression of 15-LOX-1 in colorectal carcinoma tumor samples was found in high percentage and was more prominent than in adjacent normal tissue, using both Western

Breast cancer

The interactions between 15-LOX and COX enzymes also affect the outcome of breast cancer. Indomethacin, a COX-1 and COX-2 inhibitor, decreased the growth of human breast cancer (BC) cells in nude mice, as well as slowed the rate of lung metastasis formation [41]. The levels of 12-HETE, but not 5- or 15-HETE, were elevated following indomethacin treatment, suggesting up-regulation of 12/15-LOX activity, and possibly a pro-tumorigenic role for this enzyme, in line with the stimulated metastatic

Hematologic malignancies

Examination of leukemic cells for various LOXs preceded much of the research on 15-LOX in solid tumors. This resulted from the expression of LOXs in human peripheral blood cells, both from erythroid and myeloid lineages, which are easily attainable. In an early report, bone marrow samples from chronic myelocytic leukemia (CML) were probed for the presence of LTB4 and 12-HETE using high-pressure liquid chromatography (HPLC). An increased production of LTB4 by CML bone marrow cells was found when

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

Disclosure statements

A.J. Klil-Drori wrote the manuscript. A. Ariel edited the manuscript and proofed it.

Conflict of interest statement

No conflict of interest exists for any of the authors.

Acknowledgements

This work was supported by grants from the Israel Science Foundation (number 534/09), the Nutricia Research Foundation, and the Marc Rich Foundation (to A. Ariel). A. Ariel is a recipient of the young scientist award from Teva Pharmaceuticals Ltd.

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