Eicosanoids and cancer

Abstract

Eicosanoids are 20-carbon bioactive lipids derived from the metabolism of polyunsaturated fatty acids, which can modulate various biological processes including cell proliferation, adhesion and migration, angiogenesis, vascular permeability and inflammatory responses. In recent years, studies have shown the importance of eicosanoids in the control of physiological and pathological processes associated with several diseases, including cancer. The polyunsaturated fatty acid predominantly metabolized to generate 2-series eicosanoids is arachidonic acid, which is the major n-6 polyunsaturated fatty acid found in animal fat and in the occidental diet. The three main pathways responsible for metabolizing arachidonic acid and other polyunsaturated fatty acids to generate eicosanoids are the cyclooxygenase, lipoxygenase and P450 epoxygenase pathways. Inflammation plays a decisive role in various stages of tumor development including initiation, promotion, invasion and metastasis. This review will focus on studies that have investigated the role of prostanoids and lipoxygenase-derived eicosanoids in the development and progression of different tumors, highlighting the findings that may provide insights into how these eicosanoids can influence cell proliferation, cell migration and the inflammatory process. A better understanding of the complex role played by eicosanoids in both tumor cells and the tumor microenvironment may provide new markers for diagnostic and prognostic purposes and identify new therapeutic strategies in cancer treatment.

Metabolism; Eicosanoids; Prostaglandins; Lipoxygenases; Inflammation

Biosynthesis of prostanoids

Prostanoid is a term used to define a family of biologically active lipids containing 20 carbons, which include prostaglandins (PGs) (PGD, PGE and PGF), prostacyclin (PGI) and thromboxane (TXA). These lipids are synthesized from the polyunsaturated fatty acids (PUFAs) dihomo-gamma-linolenic acid (DGLA, precursor of series 1 prostanoids), arachidonic acid (AA, precursor of series 2 prostanoids) and eicosapentaenoic acid (EPA, precursor of series 3 prostanoids). Among these precursors, AA is the most important and predominant in humans (¹-⁴).

PGs were first observed by Kurzrok and Lieb (⁵) in 1930 in human seminal fluid. This observation was confirmed by von Euler (⁶) in 1935, and twenty years later, Bergström and Sjövall (⁷) successfully purified the first PGs, which were subsequently named PGE₁ and PGF_1α. In the 1970s, it became clear that PGs have diverse effects on cells, although the mechanisms of action were unknown. It became easier to understand the action of PGs after the identification of their membrane receptors, making this area of research attractive and important (⁸,⁹).

Prostanoids are ubiquitous lipids in animal tissues and coordinate a multitude of physiological and pathological processes, either within the cells in which they are formed or in closely adjacent cells in response to specific stimuli. Under normal physiological conditions, prostanoids are involved in the relaxation and contraction of smooth muscles, regulation of blood clotting, maintenance of renal homeostasis, modulation of immune responses, inhibition and stimulation of neurotransmitter release, regulation of gastrointestinal tract secretion and motility and protection of the gastrointestinal mucosa. Prostanoids are also involved in many pathological conditions, such as inflammation, cardiovascular disease and cancer (¹⁰-¹²).

The production of prostanoids occurs through a complex enzymatic pathway (Figure 1). The first step is the activation of cytosolic phospholipase A₂ (cPLA₂), which, by hydrolysis, releases AA from membrane glycerophospholipids. PG endoperoxide H synthase 1 or 2, more commonly known as cyclooxygenase 1 or 2 (COX1 or COX2), then catalyzes a reaction in which molecular oxygen is inserted into AA. This reaction produces an unstable intermediate, PGG₂, which is rapidly converted to PGH₂ by the peroxidase activity of COX. The resulting PGH₂ is then modified by specific synthases that generate PGs and TXA, each of which has its own range of biological activities (¹³-¹⁶).

Figure 1
General overview of series-2 prostanoid biosynthesis. After being released from membrane phospholipids (PLs) by the action of cytosolic phospholipase A₂ (cPLA₂), arachidonic acid is converted by cyclooxygenase 1 or 2 (COX1 or COX2) to an unstable intermediate, prostaglandin H₂ (PGH₂), which is rapidly converted to the PGs PGE₂, PGD₂, PGF_2α, PGI₂, and thromboxane A₂ by their specific synthases. Membrane PL cleavage also results in the release of lysophosphatidylcholine, which can be converted to platelet-activating factor (PAF). Prostanoids, thromboxanes and PAF are then released from the cell and can exert a wide range of actions mediated by binding to their specific G protein-coupled receptors, EP1-4, DP1-2, FP, IP, TP and PAFR.

After synthesis, prostanoids can cross the cell membrane by simple diffusion (poorly, due to their charged nature at physiological pH) or can be transported out of the cell by members of the ABC transporter superfamily (¹⁷). In the extracellular environment, prostanoids can bind to their specific receptors to activate multiple intracellular pathways (¹⁸). There are nine different receptors for the prostanoids: DP1 and DP2 receptors for PGD₂; EP1, EP2, EP3 (splice variants) and EP4 receptors for PGE₂; FP receptor for PGF_2α; IP receptor for PGI₂; and TP receptor for TXA₂ (¹⁹-²¹).

The prostanoid receptors can be divided into three groups based on the type of G protein to which they are coupled and consequently the function of the evoked cellular responses. In the first category are the receptors related to relaxant activity, IP, EP2, EP4 and DP, which are usually coupled to Gs (stimulatory) proteins, and their activation stimulates the production of cAMP by adenylate cyclase (AC).

The second category is represented by receptors with constrictor activity, such as EP1, FP and TP, which are coupled to Gq proteins, mediating an increase in intracellular concentrations of Ca²⁺. The third group is represented only by the EP3 receptor, which is coupled to Gi (inhibitory) proteins whose activation inhibits AC, reducing cAMP concentrations. It is important to highlight that despite the specificity of most receptors related to products of the COX pathway, the TP receptor for TXA₂ can also be stimulated by the prostanoids PGE₂, PGI₂ and PGF_2α (¹,²²).

Although most prostanoids bind to cell surface receptors, in some cases, they can bind to nuclear receptors. One of the main targets is the family of peroxisome proliferator-activated receptors (PPARs), which are known to regulate lipid metabolism, cell differentiation and proliferation (²³).

The intracellular concentrations of prostanoids are controlled not only by their synthesis but also by their enzymatic degradation. Degradation begins with the transport of prostanoids from the extracellular fluid to the cytoplasm by the PG transport protein (PGT), followed by inactivation by the action of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (²⁴,²⁵).

This process gives rise to metabolites with very limited biological activities including 13,14-dihydro-15-keto PGF_2α for PGF_2α and 13,14-dihydro-15-keto PGE₂ in the case of PGE₂. PGD₂ is metabolized to PGs of the J series (PGJ₂, delta-12-PGJ₂, 15-deoxy-delta12,14 PGJ₂) or F series (9α,11β-PGF₂). TXA₂ and PGI₂ are unstable and are rapidly hydrolyzed to their inactive metabolites TXB₂ and 6-keto- PGF_1α, respectively (²⁶-²⁸).

Prostanoids and cancer

Many studies over the years have shown the ability of prostanoids to alter cancer cell proliferation and death, influence angiogenesis, increase cell migration and invasion and maintain a state of chronic inflammation (²⁸,²⁹).

Among prostanoids, PGE₂ is the most abundant PG in the body and is produced by several cells, such as fibroblasts, leukocytes and renal cells. This lipid mediator is the best known member of the PG family, as it plays an important role in several physiological systems, such as the gastrointestinal, renal, cardiovascular and reproductive system, in addition to being the main mediator of inflammation. PGE₂ is involved in pathological conditions such as cancer (²⁸,³⁰). Elevated concentrations of PGE₂ are found in several human malignancies, including colon, lung, breast and head and neck cancer, and are often associated with poor prognosis.

The biological relevance of increased production of PGE₂ in tumors has not yet been fully established. Recently, Brocard et al. (³¹) demonstrated that the addition of exogenous PGE₂ to primary glioblastoma (GBM) cultures increased the survival and proliferation of the analyzed cells. In another study, the exogenous addition of PGE₂ to the T98G human glioma cell line caused a significant increase in cell proliferation and migration, as well as a decrease in apoptosis (³²).

The increase in PGE₂ concentration is often related to the altered expression of COXs, especially COX2. The COX2 enzyme is overexpressed in cancer cells and is associated with progressive tumor growth, as well as the resistance of cancer cells to conventional chemotherapy and radiotherapy. Evidence shows that increased COX2 expression and subsequently increased downstream PGE₂ release contribute to the repopulation of tumors and consequent inefficient treatment (³⁰,³¹).

In the work of Murakami et al. (³³), increased expression of COX2 and mPGES1 in the HEK-293 cell line increased cell proliferation. In addition, increased expression of COX2 and mPGES1 in the same cells injected into the flanks of nude mice was responsible for the formation of large, well-vascularized tumors. Treatment of HCA-7 colon carcinoma cells with the mPGES1 inhibitor CAY10526 decreased PGE₂ production and attenuated cell proliferation, while increasing mPGES1 expression, PGE₂ production and cell proliferation (³⁴).

In the case of COX1, Osman and Youssef (³⁵) observed a high expression of COX1 in 62.5% of renal cancer tissues. As renal carcinoma tumor grade progressed from grade I-IV, COX1 expression progressively increased in comparison with that in normal renal tissues.

In the work of Cheng et al. (³⁶), PGE₂ promoted increased migration of Huh-7 hepatocarcinoma cells through its EP2 receptor. In the PC3 prostate cancer cell line, the migration induced by PGE₂ was mediated, in part, by EP4 (³⁷). In the CCLP1 and HuCCT1 liver cancer cell lines, the increase in migration caused by the addition of PGE₂ occurred through the EP3 receptor (³⁸).

Currently, proteins involved in the transport and degradation pathways of PGE₂ are gaining increasing attention, since the procarcinogenic effects of PGE₂ are regulated not only by their biosynthesis but also by their degradation. The internalization and inactivation of PGE₂ are performed by two distinct proteins. PGE₂ is transported into the cells through PGT and subsequently oxidized to 15-keto-PGE₂ by 15-PGDH. Both steps are necessary for the efficient inactivation of PGE₂ (³⁹). Studies have shown that PGT and 15-PGDH expression is often reduced in several neoplasms (²⁶,⁴⁰).

The analysis of 15-PGDH expression by qRT-PCR and western blotting revealed low expression in the breast cancer cell lines MCF-7, T-47D, BT-474, ZR75-1, MDA-MB-231, MDA-SK-BR-3 and BT-20 (²⁵). In high-grade neuroblastoma, low expression of 15-PGDH and consequent high concentrations of PGE₂ were identified relative to those in low-grade neuroblastomas (⁴¹). These studies suggest that changes in PGE₂ levels may play a crucial role in tumor development.

TXA₂ plays a central role in homeostasis and is increasingly implicated in cancer progression. TXA₂ production has been shown to be increased in human mammary carcinomas relative to that in normal breast tissues and was related to increased tumor size and metastatic potential, as well as the absence of estrogen (ER) and progesterone receptors (PR) (⁴²). Additionally, the TXA₂ receptor TP in triple negative breast cancer (TNBC) enhanced cell migration and invasion and activated Rho signaling, phenotypes that could be reversed using Rho-associated kinase (ROCK) inhibitors. TP also protected TNBC cells from DNA damage by negatively regulating reactive oxygen species (ROS) levels (⁴³). In prostate cancer, activation of TP led to cytoskeletal reorganization and rapid cell contraction through the activation of the small GTPase RhoA, while blockade of TP activation compromised tumor cell motility (⁴⁴,⁴⁵).

In another study, analysis of TP mRNA levels in 120 human breast tumors and 32 noncancerous mammary tissues showed that higher levels of TP transcripts were significantly associated with higher grade tumors and shorter disease-free survival (⁴⁶). High expression levels of TP have also been observed in lung, bladder and prostate cancer cell lines, leading to increased cell proliferation, migration and invasion capacity (⁴⁴,⁴⁵,⁴⁷). In lung cancer cells, thromboxane A₂ synthase (TXAS) inhibited apoptosis via negative regulation of ROS production in the lung (⁴⁸). The use of furegrelate, a potent inhibitor of TXAS, in addition to inhibiting the migration process, decreased adhesion, increased apoptosis, decreased tumor growth in vivo and increased sensitivity to radiation in glioma-derived cells (⁴⁹-⁵²).

In the literature, PGF_2α is related to increased migration and invasion observed in colorectal carcinoma cells (⁵³). In prostate cancer, the overexpression of aldo-keto reductase 1C3 (AKR1C3), an enzyme involved in PG metabolism, resulted in the accumulation of PGF_2α, which not only promotes prostate cancer cell proliferation but also enhances prostate cancer cell resistance to radiation (⁵⁴).

Keightley et al. (⁵⁵) observed that in endometrial cancer, PGF_2α induced activation of the FP receptor in the epithelial cells of endometrial adenocarcinoma, resulting in the stimulation of the calmodulin-NFAT signaling pathway. This signaling pathway leads to elevated ADAMTS1, which functions in an autocrine/paracrine manner to promote epithelial cell invasion and in a paracrine manner to inhibit endothelial cell proliferation (⁵⁵).

In endometrial cancer, the binding of PGF_2α to the FP receptor enhanced cell proliferation, migration and angiogenesis of carcinoma cells through the activation of the extracellular signal-regulated kinase (ERK) pathway (⁵⁶). Müller et al. (⁵⁷) also found downregulation of the FP receptor in skin papillomas in mouse models of cancer, and its level of expression was inversely correlated with PGF_2α production, suggesting that PGF_2α regulates levels of the FP receptor in the squamous epithelium. Scott et al. (⁵⁸) also demonstrated that in melanoma, the concentrations of PGF_2α were higher than those in normal melanocytes. These results show that the binding of PGF_2α to the FP receptor activates signals that stimulate a differentiated phenotype. In addition, PGF_2α concentration was found to be consistently higher in breast cancer than in benign and non-neoplastic tissues (⁵⁹,⁶⁰).

Evidence from the literature suggests that PGI₂ may protect against cancer development by inhibiting tumor growth, angiogenesis, invasion and metastasis, and thus can be considered a potential chemopreventive agent. Studies have indicated that the lungs of mice treated with PGI₂ had 40-50 times fewer metastatic nodes than lungs of mice treated with the positive control . The same study showed that treatment of mice with PGI₂ resulted in a 10% decrease in the adhesion of metastatic cells to endothelial tubules (⁶¹).

Preclinical chemoprevention studies showed that pulmonary PGI synthase (PGIS) overexpression and elevated PGI₂ concentrations protect against lung tumorigenesis in a variety of murine tumorigenesis models, including those established by exposure to tobacco smoke (⁶²,⁶³). The administration of tranylcypromine, which inhibits PGIS, has been shown to reduce cancer multiplicity in murine carcinogenesis models, indicating that the inhibition of this enzyme may be useful in the chemoprevention of breast cancer (⁶⁴).

In primary human lung tumor samples, loss of PGIS mRNA was observed relative to that in matched normal controls (⁶⁵). These findings are in agreement with the study by Stearman et al. (⁶⁶), in which gene expression analysis of non-small cell lung cancer (NSCLC) showed a loss of PGIS in human lung tumor samples. However, a small group of adenocarcinoma patients whose lung tumors retained PGIS expression were found to have significantly enhanced survival. A statistically significant correlation was also observed in head and neck squamous cell carcinoma. Patients who expressed high levels of PGIS in head and neck squamous cell carcinoma tissues had a higher 5-year survival rate than patients with low levels of PGIS (⁶⁷).

In the case of breast cancer, analysis revealed that the expression of PGIS is associated with a reduction in patient survival (⁶⁸). On the other hand, the expression of the prostacyclin receptor IP appears to indicate an angiogenic phenotype of tumor endothelial cells according to a study in which migration and tube formation were inhibited by the IP receptor antagonist RO1138452 (⁶⁹). These apparently contradictory actions of PGI₂ on cell survival may indicate that its effects are highly dependent on the specific cellular environment.

The implications of PGD₂ production in tumor development and progression have remained largely unexplored. The few studies on this prostanoid consider PGD₂ to have an antitumor activity (⁷⁰). This hypothesis is supported by studies showing that elevated levels of PGD₂ result in relatively few metastatic foci in rat lungs, inhibition of leukemic cell growth and Ehrlich tumor growth, and decreased metastatic potential in melanomas (⁷¹-⁷³).

In a study by Park et al. (⁷⁴), which evaluated the possible influence of PGD₂ on the development of intestinal adenomas, a 50% increase in intestinal adenomas was shown in the ApcMin/knockout mouse model for the hematopoietic PGD synthase (H-PGDS) enzyme, whereas in the ApcMin/+ mouse model with high expression of H-PGDS, an approximately 80% reduction in the adenomas was observed.

In gliomas, lower protein and mRNA levels of lipocalin-PGD synthase (L-PGDS), the main PGDS produced in neurons and glial cells, were observed in different GBM samples than in normal brain tissues (⁷⁵). Moreover, the exogenous addition of PGD₂ to the A172 and C6 lines resulted in a decrease in the proliferative capacity of the cells (⁷⁵,⁷⁶). Recent studies have confirmed that PGD₂ can inhibit glioma cell proliferation. However, at lower physiological concentrations of PGD₂, U87MG, U251MG and A172 glioma cell proliferation and migration were stimulated rather than inhibited (⁷⁷)

The correlation between hepatic metastasis and PGD₂ concentration in human cancer tissues has also been studied. The mean PGD₂ concentration in primary cancer tissues was significantly lower in the group with hepatic metastasis than in the group without hepatic metastasis (⁷⁸). Using gastric cancer cells, Fukuoka et al. (⁷⁹) observed that PGD₂ significantly decreased the proliferation of tumor cells via the PPARγ pathway. In 277 human gastric tumors, L-PGDS-positive cases were significantly correlated with PPARγ-positive cases. In recent years, several studies have shown that PGD₂ has antiproliferative activities and can induce cellular apoptosis via the activation of caspase-dependent pathways in human leukemia cells (⁸⁰,⁸¹) and colon cancer cells (⁷⁸).

In a study with A549 lung carcinoma cells, PGD₂ induced cell death through the intrinsic apoptotic pathway, and similar results were also found with another lung carcinoma cell line, H2199. Moreover, the generation of 15-deoxy-delta12,14 PGJ₂, a metabolite of PGD₂, seems to be the key factor responsible for the apoptosis observed in A549 cells (⁸²).

LIPOXYGENASE PATHWAY

5-Lipoxygenase (5-LOX)

The 5-lipoxygenase (5-LOX) pathway is the most well characterized among the lipoxygenase pathways. It begins with the insertion of molecular oxygen and the formation of a hydroperoxyl group at carbon 5 of the AA chain, resulting in 5-hydroperoxyeicosatetraenoic acid (5-HpETE) that can be converted to 5-hydroxyeicosatetraenoic acid (5-HETE) (⁸³). 5-HpETE can also be converted to leukotriene A₄ (LTA₄), a leukotriene with no known biological activity that serves as a precursor for the synthesis of biologically active leukotrienes. The conversion of LTA₄ by the enzyme LTA₄ hydrolase (LTA₄H) results in the production of leukotriene B₄ (LTB₄), while the enzyme LTC₄ synthase produces leukotriene C₄ (LTC₄) (Figure 2). LTC₄, in turn, is the precursor of the other members of the cysteinyl leukotrienes including LTD₄ and LTE₄. (¹²,⁸⁴). Leukotrienes and 5-HETE have similar effects on neutrophils and other leukocytes, serving as potent chemoattractants in addition to modulating adhesion, migration and degranulation. However, little is known about the specific receptors of 5-HETE (⁸⁵). Several studies indicate that 5-HETE is a substrate for 5-hydroxyeicosanoid dehydrogenase (5-HEDH), resulting in the synthesis of the non-classical eicosanoid 5-oxo-eicosatetraenoic acid (5-oxoETE), with a much more potent effect than 5-HETE on neutrophils (⁸⁶,⁸⁷).

Figure 2
General overview of leukotriene biosynthesis. After being released from membrane phospholipids (PLs) by the action of cytosolic phospholipase A₂ (cPLA₂), arachidonic acid is converted by the lipoxygenases (LOXs) 5-LOX, 12-LOX and 15-LOX-1 or 15-LOX-2 to the corresponding hydroperoxyeicosatetraenoic acid (HpETE) - 5-HpETE, 12-HpETE or 15-HpETE. These are rapidly converted to hydroxyeicosatetraenoic acids (HETEs) - 5-HETE, 12-HETE and 15-HETE. In addition, 5-HpETE is catalyzed by 5-LOX to form the unstable leukotriene LTA₄, which, through the action of LTA₄ hydrolase, results in the synthesis of LTB₄. Alternatively, LTA₄ can be converted into the cysteinyl leukotriene LTC₄ by the action of LTC₄ synthase. LTC₄ can then be converted to LTD₄ and LTE₄. Linoleic acid (LA) can be metabolized by 15-LOX producing 13-hydroperoxyoctadecadienoic acid (13-HpODE), which is then metabolized to 13-hydroxyoctadecadienoic acid (13-HODE). 15-HpETE can also be catalyzed by 5-LOX, often transcellularly, to produce lipoxin A₄ (LXA₄). Leukotrienes and HETEs are then released from the cell and can exert a wide range of actions mediated by binding to their specific receptors, BLT1-BLT2, CysLTR1-CysLTR2 and 12-HETER.

Lepley et al. (⁸⁸) were the first to show the mechanisms controlling the activation of 5-LOX, identifying the presence of phosphorylated 5-LOX in activated neutrophils, thereby correlating the activity with its phosphorylation. The regulation of the enzymatic activity of 5-LOX depends on its interaction with Ca²⁺, interaction with the FLAP protein and 5-LOX translocation through cellular compartments. Additionally, 5-LOX is phosphorylated at residues Ser271, Ser663 and Ser523 by the activity of MAPKAP2 (Ser271), ERK2 (Ser663) and protein kinase A (PKA) (Ser523). Several additional phosphorylation sites, at Tyr42, Tyr53 and either Tyr94 or Tyr445, were recently identified by Markoutsa et al. (⁸⁹). Once bound to Ca²⁺, 5-LOX translocates to the nuclear envelope. The FLAP membrane protein, with affinity for AA, is found in the nuclear envelope. The exact mechanisms that regulate the relationship between FLAP and 5-LOX are still not fully understood, but once 5-LOX is activated and is present in the nuclear envelope, FLAP acts as a substrate carrier that presents AA to the 5-LOX enzyme (⁹⁰-⁹³).

The expression of 5-LOX is usually low or absent in normal tissues but detected in response to pathological conditions in cells derived from bone marrow, such as granulocytes, macrophages, and B lymphocytes (⁹⁴). The leukotrienes and 5-HETE generated by 5-LOX play an important role in the inflammatory process associated with numerous diseases including cancer, allergic asthma, dermatitis, rhinitis, arthritis, atherosclerosis, ischemia and septic shock (⁹⁵,⁹⁶).

The relationship between 5-LOX and cancer has been explored in the literature over the past two decades. In the late 1990s, an in vitro study with PC-3 and LNCaP prostate cancer cell lines showed that MK886, a FLAP-binding 5-LOX inhibitor, leads to apoptosis due to the inhibition of 5-LOX activities. Furthermore, the addition of 5-HETE or 5-oxo-ETE was sufficient to prevent the effects of MK886 (⁹⁷).

Later studies identified 5-LOX as a potential biomarker for malignancy. Larré et al. (⁹⁸) found higher concentrations of LTB₄ in prostate carcinoma tissues than in peritumoral tissues. Another study with 42 patients analyzed 5-LOX expression by immunohistochemistry in brain tumor samples. With the exception of three low-grade gliomas, all samples showed 5-LOX expression (⁹⁹). Additionally, 5-LOX expression in 111 colon adenomas showed a correlation with high risk factors that traditionally are markers for malignant transformation to colorectal adenocarcinoma, thereby providing clues about the link between 5-LOX and colorectal cancer malignancy (¹⁰⁰). Leukotriene receptors were also found to be altered in cancer, with increased BLT1 expression in prostate (¹⁰¹) and colon carcinoma (¹⁰²), and the pharmacological blocking of BLT1 activity was sufficient to reduce cell proliferation.

The data accumulated so far, notably in prostate and colorectal carcinoma, points to an important role of 5-LOX during tumor development and progression. Recently, the physiological role of 5-LOX products as chemoattractants and stimulators of myeloid cells was correlated with their role in cancer progression (¹⁰³). Interestingly, evidence shows that 5-LOX activity in mast cells is important for the promotion of abnormal cell proliferation during intestinal polyposis in mice (¹⁰⁴). In another recent study, the importance of microenvironment-derived 5-LOX products was assessed by injecting Lewis lung carcinoma cells into 5-LOX-deficient rats to compare tumor growth with that in control rats (¹⁰⁵). The tumor microenvironment of 5-LOX-deficient rats showed an increase in angiogenesis and reduction in neutrophils and cytotoxic T cells, leading to larger tumors than in control rats. Although the importance of 5-LOX in tumor development and progression is convincing, the roles played by 5-LOX metabolism from the tumor microenvironment versus the tumor cells are still not fully elucidated.

12-Lipoxygenase (12-LOX)

12-Lipoxygenase (12-LOX) is another enzyme in the lipoxygenase family, responsible for the insertion of molecular oxygen and the formation of a hydroperoxyl group at carbon 12 of the AA chain to form 12-HpETE. Similar to 5-HpETE, 12-HpETE has no known biological activity, serving as a precursor for 12-HETE production (Figure 2).

The former name 12-LOX platelet-type was due to the detection of 12-HETE in platelets during the 1970s, and 12-HETE was subsequently characterized as an endothelial retraction factor (¹⁰⁶). 12-LOX is expressed in smooth muscle cells, keratinocytes, endothelial cells, macrophages and platelets, and the physiological roles of 12-HETE are associated with lymphatic vessel permeability and smooth muscle cell retraction to modulate vessel contraction (¹⁰⁷). Furthermore, 12-HETE displays both antithrombotic and prothrombotic activities through the modulation of platelet aggregation (¹⁰⁸-¹¹⁰).

One of the earliest correlations between 12-LOX and cancer was reported in a study with 112 samples from radical prostatectomy, where an increase in 12-LOX expression was found to correlate with advanced stage, poor differentiation and invasive potential according to pathological stage, histological grade and surgical status (¹¹¹). Since then, many studies have found that 12-HETE is strongly correlated with metastasis. Similar to the activities of other eicosanoids, 12-HETE activities are triggered through its recognition by specific receptors on the plasma membrane. A specific G protein-coupled receptor, GPR31, also called 12-HETE receptor (12-HETER), was recently identified (¹¹²). The activation of 12-HETER leads to protein kinase C (PKC) activation, stimulating the PKC/ERK1/2 pathway and altering cell proliferation (¹¹³). Furthermore, 12-HETE release downregulates E-cadherin and stimulates endothelial cell migration, increasing lymphatic vessel permeability (¹¹⁴). Additionally, a similar mechanism is responsible for increased endothelial barrier permeability by 12-HETE (¹¹⁵). By altering vascular permeability, 12-HETE plays a key role in neutrophil migration through the endothelial barrier and also modulates RhoA-dependent migration (¹¹⁶, ¹¹⁷).

By acting on vascular permeability, cell attachment and cell migration, 12-HETE can facilitate tumor cell migration through the endothelial barrier, thereby facilitating metastasis. Chen et al. (¹¹⁸) showed a correlation between 12-HETE production and metastasis by treating C57BL/6J mice with the selective 12-LOX inhibitor N-benzyl-N-hydroxy-5-phenylpentamidine (BHPP). A reduction in lung colonies was observed in animals treated with BHPP. Another study showed in vitro that the same inhibitor could attenuate endothelial cell migration and proliferation in response to angiogenic factors. In addition, 12-LOX inhibition significantly reduced angiogenesis in vivo. (¹¹⁹). In the MKN-28 gastric cancer cell line, inhibition of 12-LOX with baicalein induced apoptosis (¹²⁰). Not only the inhibition but also the upregulation of 12-LOX in colorectal cancer cells led to changes in proliferation and migration. The induced overexpression of 12-LOX in these cells increased migration and metastasis in mice (¹²¹). Reinforcing the role of 12-LOX in metastasis, the secretion of 12-HETE by MCF-7 breast cancer cell spheroids co-cultured over a lymphatic endothelial monolayer induced circular discontinuities due to endothelial retraction (¹²²). As previously mentioned, these effects on endothelial cells have been proposed to be an important step in 12-HETE-stimulated metastasis. More recently, in MCF-7 or MDA-MB-231 breast cancer cell spheroids co-cultured with lymphatic endothelial cells, 12-HETE was shown to increase intracellular Ca²⁺ release in endothelial cells, inducing a Ca²⁺-dependent disruption in their barrier functions and increasing the number of discontinuities in the endothelial monolayer (¹¹⁴,¹²³).

15-Lipoxygenases (15-LOX-1 and 15-LOX-2)

Human 15-lipoxygenases (15-LOXs) are a subfamily formed by two isoforms: 15-LOX-1 and 15-LOX-2. 15-LOX-1 (also known as 15-LOX reticulocyte-type) was initially identified in rabbit reticulocytes and is normally expressed in eosinophils, reticulocytes and respiratory epithelia (¹²⁴). Both 15-LOX-1 and 15-LOX-2 were classified and named based on their ability to insert molecular oxygen and form a hydroperoxyl group at carbon 15 of AA, producing 15-HpETE, which can be reduced to 15-HETE (Figure 2). Although 15-LOX-1 and 15-LOX-2 can both use AA as a substrate, both molecules can also oxygenate the 18-carbon fatty acid linoleic acid (LA) at carbon 13 to produce 13-hydroperoxyoctadecadienoic acid (13-HpODE) that can then be reduced to 13-hydroxyoctadecadienoic acid (13-HODE) (¹²⁵). However, the substrate specificity of the two enzymes is not identical. The 15-LOX-1 enzyme has a higher affinity for LA (therefore producing 13-HODE), while 15-LOX-2 shows a preference for AA (therefore producing 15-HETE) and poorly metabolizes LA (¹²⁶,¹²⁷).

Due to differences between their activities and differences in substrates/products, both 15-LOX-1 and 15-LOX-1-2 are correlated with many pathological processes associated with chronic inflammation, such as in asthma, atherosclerosis, insulin resistance and cancer (¹²⁸-¹³⁰). The preference of 15-LOX-1 to metabolize LA to 13-HODE has been correlated in many studies with a protective effect in inflammatory diseases. Depletion of 15-LOX-1 is proposed to exacerbate inflammation in atherosclerosis, encephalomyelitis, asthma and osteoarthritis (¹³¹-¹³⁴). The roles of 15-HETE, on the other hand, are associated with inflammatory processes and angiogenesis. Zhang et al. (¹³⁵) demonstrated that 15-HETE stimulation led to the migration and formation of endothelial cell tubes in vitro in a process dependent on PI3K-AKT-mTOR activation. Wang et al. (¹³⁶) showed the functional role of 15-HETE and the 15-LOX pathway in angiogenesis in a mouse stroke model, consistent with the literature in which an increase in 15-HETE concentrations followed post-ischemic hypoxia in neural tissues (¹³⁷-¹³⁹).

Regarding the roles of 15-LOX-1 and 15-LOX-2 in cancer, one of the first studies to propose an antitumorigenic role for 15-LOX-1 showed a decrease in 13-HODE production and 15-LOX-1 expression in 18 colon cancer samples compared with those in normal colon samples (¹⁴⁰). Several subsequent studies have provided support for the antitumorigenic role of 13-HODE in specific tumors. Shureiqi et al. (¹⁴¹) showed in colorectal cancer cell lines that treatment with the specific COX2 inhibitor celecoxib caused apoptosis following an increase in 13-HODE concentration. Interfering with 13-HODE production by silencing 15-LOX-1 protected celecoxib-treated cells from death. Another study using HCT-116 and HT-29 colon cancer cells, which do not have detectable levels of 15-LOX-1, showed that the induced expression of 15-LOX-1 significantly decreased cell proliferation and increased apoptosis. Furthermore, a decrease in adhesion to fibronectin, anchorage-independent growth on soft agar, and migratory and invasive capacity on Matrigel was observed to strongly associate 15-LOX-1 activity with the inhibition of migration and metastatic capacity in colon cancer (¹⁴²). This association between 15-LOX-1 and an antitumorigenic role was also reported in a study with weaker 15-LOX-1 in 120 breast cancer tissue samples than in normal tissues, indicating that the loss of 15-LOX-1 expression may be correlated with tumorigenesis (¹⁴³). Additionally, in pancreatic cancer cell lines and pancreatic carcinoma samples (n=12), 15-LOX-1 expression was found to be reduced. Stable expression 15-LOX-1 in pancreatic cancer cell lines was found to reduce proliferation (¹⁴⁴). Exogenous treatment of 13-HODE in breast and colorectal cancer cells also caused a reduction in cell viability (¹⁴¹,¹⁴⁵).

Although a number of studies suggest the antitumorigenic role of 13-HODE, others show a different role for 15-LOX-1 and 13-HODE in the prostate. The prostate cancer cell lines PC-3 and LNCaP have high concentrations of 13-HODE. Moreover, treatment of PC-3 cells with 13-HODE led to enhanced MAP kinase (MAPK) pathway signaling, resulting in increased proliferation (¹⁴⁶). Kelavkar et al. (¹⁴⁷) observed strong 15-LOX-1 expression in 48 prostatectomy samples with varying degrees of malignancy, and the expression level of 15-LOX-1 was positively correlated with p53 mutations and the degree of malignancy. Sen et al. (¹⁴⁸) evaluated the adenovirus-mediated overexpression of 15-LOX-1 by injecting adenoviruses harboring 15-LOX-1 with green fluorescent protein (GFP) or GFP alone into the dorsolateral prostates of C57BL/6 mice. After 90 days, the expression of 15-LOX-1 resulted in the development of a prostate intraepithelial neoplasia-like phenotype, increasing the expression of Ki-67 as well as the angiogenic markers FGF-a and FGF-b. The study thus proved that the forced overexpression of 15-LOX-1 in normal prostate tissue is enough to increase cell proliferation and upregulate genes associated with malignancy.

While 13-HODE and 15-LOX-1 are generally believed to play an antitumorigenic role, data on 15-LOX-2 are less conclusive. Most research data available on 15-HETE refers to the 12/15-LOX rodent isoform, which can metabolize AA to form both 12-HETE and 15-HETE, making it more difficult to correlate the data with human 15-LOX-2 (¹⁴⁹). Despite previous in vitro results reporting the overexpression of 15-LOX-2 in breast cancer cell lines (¹⁵⁰), in breast tumor biopsy samples (n=120), 15-LOX-2 expression was decreased in comparison with that in normal tissues (¹⁴³). In lung cancer, a recent study treated NSCLC cell lines with both 13-HODE and 15-HETE and found a decrease in proliferation, induction of apoptosis and activation of peroxisome proliferator-activated receptor γ (PPARγ) (¹⁵¹). While 15-LOX-1 is overexpressed and 13-HODE is present at higher concentrations in prostate cancer, 15-LOX-2 and 15-HETE are reportedly decreased in high-grade prostate neoplasia (¹⁵²), suggesting opposing roles for 15-LOX-1 and 15-LOX-2 in prostate cancer. The work of Hsi et al. (¹⁴⁶) corroborated these opposite effects of 15-LOXs by showing that in the PC-3 prostate cell line, 13-HODE upregulated the activity of MAPK and increased the phosphorylation of PPARγ, while 15-HETE downregulated MAPK and decreased PPARγ phosphorylation.

The role of eicosanoids and their degradation products in the development and progression of cancer has been a target of investigations for many years. Despite considerable study, many controversies still exist in the literature in relation to individual eicosanoids in specific tumor settings. As we have highlighted in this review, many eicosanoids are considered to be tumorigenic, some are believed to be antitumorigenic, and several have mixed properties dependent on the tumor type in question. Clearly, the complex interplay among the eicosanoid pathways, their products, their receptors and the subsequent intracellular signaling pathways that are activated need to be better delineated and remain important subjects for future studies. An important goal in these studies will be to provide a better understanding of the complex role played by eicosanoids in both tumor cells and the tumor microenvironment. Such detailed information could provide new diagnostic and/or prognostic markers and identify new therapeutic strategies in cancer treatment.

ACKNOWLEDGMENTS

We are grateful for the financial support from FAPESP (São Paulo, Brazil; number: 2015/08777-0).

REFERENCES

• ¹
  Bos CL, Richel DJ, Ritsema T, Peppelenbosch MP, Versteeg HH. Prostanoids and prostanoid receptors in signal transduction. Int J Biochem Cell Biol. 2004;36(7):1187-205, http://dx.doi.org/10.1016/j.biocel.2003.08.006
  » http://dx.doi.org/10.1016/j.biocel.2003.08.006
• ²
  Van Dorpd DA, Beerthuis RK, Nugteren DH, Vonkeman H. Enzymatic conversion of all-cis-polyunsaturated fatty acids into prostaglandins. Nature. 1964;203:839-41, http://dx.doi.org/10.1038/203839a0
  » http://dx.doi.org/10.1038/203839a0
• ³
  Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, et al. Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway. J Lipid Res. 2014;55(6):1150-64, http://dx.doi.org/10.1194/jlr.M047357
  » http://dx.doi.org/10.1194/jlr.M047357
• ⁴
  Simopoulos AP. An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity. Nutrients. 2016;8(3):128, http://dx.doi.org/10.3390/nu8030128
  » http://dx.doi.org/10.3390/nu8030128
• ⁵
  Kurzrok R, Lieb CC. Biochemical Studies of Human Semen. II. The Action of Semen on the Human Uterus. Proc Soc Exp Biol Med. 1930;26:268-72, http://dx.doi.org/10.3181/00379727-28-5265
  » http://dx.doi.org/10.3181/00379727-28-5265
• ⁶
  Von Euler US. On the specific vaso-dilating and plain muscle stimulating substances from accessory genital glands in man and certain animals (prostaglandin and vesiglandin). J Physiol. 1936;88(2):213-34, http://dx.doi.org/10.1113/jphysiol.1936.sp003433
  » http://dx.doi.org/10.1113/jphysiol.1936.sp003433
• ⁷
  Bergström S, Sjövall J. The Isolation of Prostaglandin. Acta Chem Scand. 1957; 11(6):1086, http://dx.doi.org/10.3891/acta.chem.scand.11-1086
  » http://dx.doi.org/10.3891/acta.chem.scand.11-1086
• ⁸
  Gryglewski RJ. Prostacyclin among prostanoids. Pharmacol Rep. 2008;60(1):3-11.
• ⁹
  Samuelsson B. Introduction: new trends in prostaglandin research. Adv Prostaglandin Thromboxane Res. 1976;1:1-6.
• ¹⁰
  Khanapure SP, Garvey DS, Janero DR, Letts LG. Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers. Curr Top Med Chem. 2007;7(3):311-40, http://dx.doi.org/10.2174/156802607779941314
  » http://dx.doi.org/10.2174/156802607779941314
• ¹¹
  Nathoo N, Barnett GH, Golubic M. The eicosanoid cascade: possible role in gliomas and meningiomas. J Clin Pathol. 2004;57(1):6-13, http://dx.doi.org/10.1136/jcp.57.1.6
  » http://dx.doi.org/10.1136/jcp.57.1.6
• ¹²
  Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer. 2010;10(3):181-93, http://dx.doi.org/10.1038/nrc2809
  » http://dx.doi.org/10.1038/nrc2809
• ¹³
  Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004;56(3):387-437, http://dx.doi.org/10.1124/pr.56.3.3
  » http://dx.doi.org/10.1124/pr.56.3.3
• ¹⁴
  Murakami M, Kudo I. Recent advances in molecular biology and physiology of the prostaglandin E2-biosynthetic pathway. Prog Lipid Res. 2004;43(1):3-35, http://dx.doi.org/10.1016/S0163-7827(03)00037-7
  » http://dx.doi.org/10.1016/S0163-7827(03)00037-7
• ¹⁵
  Arima M, Fukuda T. Prostaglandin D2 and T(H)2 inflammation in the pathogenesis of bronchial asthma. Korean J Intern Med. 2011;26(1):8-18, http://dx.doi.org/10.3904/kjim.2011.26.1.8
  » http://dx.doi.org/10.3904/kjim.2011.26.1.8
• ¹⁶
  Smith WL, Urade Y, Jakobsson PJ. Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis. Chem Rev. 2011;111(10):5821-65, http://dx.doi.org/10.1021/cr2002992
  » http://dx.doi.org/10.1021/cr2002992
• ¹⁷
  Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, et al. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003;100(16):9244-9, http://dx.doi.org/10.1073/pnas.1033060100
  » http://dx.doi.org/10.1073/pnas.1033060100
• ¹⁸
  Kochel TJ, Fulton AM. Multiple drug resistance-associated protein 4 (MRP4), prostaglandin transporter (PGT), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) as determinants of PGE2 levels in cancer. Prostaglandins Other Lipid Mediat. 2015;116-117:99-103, http://dx.doi.org/10.1016/j.prostaglandins.2014.11.003
  » http://dx.doi.org/10.1016/j.prostaglandins.2014.11.003
• ¹⁹
  Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999;79(4):1193-226, http://dx.doi.org/10.1152/physrev.1999.79.4.1193
  » http://dx.doi.org/10.1152/physrev.1999.79.4.1193
• ²⁰
  Narumiya S, FitzGerald GA. Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest. 2001;108(1):25-30, http://dx.doi.org/10.1172/JCI200113455
  » http://dx.doi.org/10.1172/JCI200113455
• ²¹
  Tsuboi K, Sugimoto Y, Ichikawa A. Prostanoid receptor subtypes. Prostaglandins Other Lipid Mediat. 2002;68-69:535-56, http://dx.doi.org/10.1016/S0090-6980(02)00054-0
  » http://dx.doi.org/10.1016/S0090-6980(02)00054-0
• ²²
  Coleman RA, Smith WL, Narumiya S. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev. 1994;46(2):205-29.
• ²³
  Wang D, DuBois RN. Measurement of eicosanoids in cancer tissues. Methods Enzymol. 2007;433:27-50, http://dx.doi.org/10.1016/S0076-6879(07)33002-4
  » http://dx.doi.org/10.1016/S0076-6879(07)33002-4
• ²⁴
  Schuster VL. Prostaglandin transport. Prostaglandins Other Lipid Mediat. 2002;68-69:633-47, http://dx.doi.org/10.1016/S0090-6980(02)00061-8
  » http://dx.doi.org/10.1016/S0090-6980(02)00061-8
• ²⁵
  Wolf I, O’Kelly J, Rubinek T, Tong M, Nguyen A, Lin BT, et al. 15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. Cancer Res. 2006;66(15):7818-23, http://dx.doi.org/10.1158/0008-5472.CAN-05-4368
  » http://dx.doi.org/10.1158/0008-5472.CAN-05-4368
• ²⁶
  Holla VR, Backlund MG, Yang P, Newman RA, DuBois RN. Regulation of prostaglandin transporters in colorectal neoplasia. Cancer Prev Res (Phila). 2008;1(2):93-9.
• ²⁷
  Korbecki J, Baranowska-Bosiacka I, Gutowska I, Chlubek D. Cyclooxygenase pathways. Acta Biochim Pol. 2014;61(4):639-49.
• ²⁸
  Wang D, Dubois RN. Prostaglandins and cancer. Gut. 2006;55(1):115-22, http://dx.doi.org/10.1136/gut.2004.047100
  » http://dx.doi.org/10.1136/gut.2004.047100
• ²⁹
  Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-7, http://dx.doi.org/10.1038/nature01322
  » http://dx.doi.org/10.1038/nature01322
• ³⁰
  Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 2009;30(3):377-86, http://dx.doi.org/10.1093/carcin/bgp014
  » http://dx.doi.org/10.1093/carcin/bgp014
• ³¹
  Brocard E, Oizel K, Lalier L, Pecqueur C, Paris F, Vallette FM, et al. Radiation-induced PGE2 sustains human glioma cells growth and survival through EGF signaling. Oncotarget. 2015;6(9):6840-9, http://dx.doi.org/10.18632/oncotarget.3160
  » http://dx.doi.org/10.18632/oncotarget.3160
• ³²
  Gomes RN, Colquhoun A. E series prostaglandins alter the proliferative, apoptotic and migratory properties of T98G human glioma cells in vitro. Lipids Health Dis. 2012;11:171, http://dx.doi.org/10.1186/1476-511X-11-171
  » http://dx.doi.org/10.1186/1476-511X-11-171
• ³³
  Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, et al. Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem. 2000;275(42):32783-92, http://dx.doi.org/10.1074/jbc.M003505200
  » http://dx.doi.org/10.1074/jbc.M003505200
• ³⁴
  Kamei D, Murakami M, Nakatani Y, Ishikawa Y, Ishii T, Kudo I. Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis. J Biol Chem. 2003;278(21):19396-405, http://dx.doi.org/10.1074/jbc.M213290200
  » http://dx.doi.org/10.1074/jbc.M213290200
• ³⁵
  Osman WM, Youssef NS. Combined use of COX-1 and VEGF immunohistochemistry refines the histopathologic prognosis of renal cell carcinoma. Int J Clin Exp Pathol. 2015;8(7):8165-77.
• ³⁶
  Cheng SY, Zhang H, Zhang M, Xia SK, Bai XM, Zhang L, et al. Prostaglandin E2 receptor EP2 mediates Snail expression in hepatocellular carcinoma cells. Oncol Rep. 2014;31(5):2099-106, http://dx.doi.org/10.3892/or.2014.3074
  » http://dx.doi.org/10.3892/or.2014.3074
• ³⁷
  Huang HF, Shu P, Murphy TF, Aisner S, Fitzhugh VA, Jordan ML. Significance of divergent expression of prostaglandin EP4 and EP3 receptors in human prostate cancer. Mol Cancer Res. 2013;11(4):427-39, http://dx.doi.org/10.1158/1541-7786.MCR-12-0464
  » http://dx.doi.org/10.1158/1541-7786.MCR-12-0464
• ³⁸
  Du M, Shi F, Zhang H, Xia S, Zhang M, Ma J, et al. Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor. Oncol Rep. 2015;34(2):715-26, http://dx.doi.org/10.3892/or.2015.4043
  » http://dx.doi.org/10.3892/or.2015.4043
• ³⁹
  Nomura T, Lu R, Pucci ML, Schuster VL. The two-step model of prostaglandin signal termination: in vitro reconstitution with the prostaglandin transporter and prostaglandin 15 dehydrogenase. Mol Pharmacol. 2004;65(4):973-8, http://dx.doi.org/10.1124/mol.65.4.973
  » http://dx.doi.org/10.1124/mol.65.4.973
• ⁴⁰
  Ichikawa A, Sugimoto Y, Negishi M. Molecular aspects of the structures and functions of the prostaglandin E receptors. J Lipid Mediat Cell Signal. 1996;14(1-3):83-7, http://dx.doi.org/10.1016/0929-7855(96)00512-3
  » http://dx.doi.org/10.1016/0929-7855(96)00512-3
• ⁴¹
  Larsson K, Kock A, Idborg H, Arsenian Henriksson M, Martinsson T, Johnsen JI, et al. COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset. Proc Natl Acad Sci U S A. 2015;112(26):8070-5, http://dx.doi.org/10.1073/pnas.1424355112
  » http://dx.doi.org/10.1073/pnas.1424355112
• ⁴²
  Karmali RA, Welt S, Thaler HT, Lefevre F. Prostaglandins in breast cancer: relationship to disease stage and hormone status. Br J Cancer. 1983;48(5):689-96, http://dx.doi.org/10.1038/bjc.1983.251
  » http://dx.doi.org/10.1038/bjc.1983.251
• ⁴³
  Orr K, Buckley NE, Haddock P, James C, Parent JL, McQuaid S, et al. Thromboxane A2 receptor (TBXA2R) is a potent survival factor for triple negative breast cancers (TNBCs). Oncotarget. 2016;7(34):55458-55472, http://dx.doi.org/10.18632/oncotarget.10969
  » http://dx.doi.org/10.18632/oncotarget.10969
• ⁴⁴
  Nie D, Guo Y, Yang D, Tang Y, Chen Y, Wang MT, et al. Thromboxane A2 receptors in prostate carcinoma: expression and its role in regulating cell motility via small GTPase Rho. Cancer Res. 2008;68(1):115-21, http://dx.doi.org/10.1158/0008-5472.CAN-07-1018
  » http://dx.doi.org/10.1158/0008-5472.CAN-07-1018
• ⁴⁵
  Nie D, Che M, Zacharek A, Qiao Y, Li L, Li X, et al. Differential expression of thromboxane synthase in prostate carcinoma: role in tumor cell motility. Am J Pathol. 2004;164(2):429-39, http://dx.doi.org/10.1016/S0002-9440(10)63133-1
  » http://dx.doi.org/10.1016/S0002-9440(10)63133-1
• ⁴⁶
  Watkins G, Douglas-Jones A, Mansel RE, Jiang WG. Expression of thromboxane synthase, TBXAS1 and the thromboxane A2 receptor, TBXA2R, in human breast cancer. Int Semin Surg Oncol. 2005;2:23, http://dx.doi.org/10.1186/1477-7800-2-23
  » http://dx.doi.org/10.1186/1477-7800-2-23
• ⁴⁷
  Moussa O, Yordy JS, Abol-Enein H, Sinha D, Bissada NK, Halushka PV, et al. Prognostic and functional significance of thromboxane synthase gene overexpression in invasive bladder cancer. Cancer Res. 2005;65(24):11581-7, http://dx.doi.org/10.1158/0008-5472.CAN-05-1622
  » http://dx.doi.org/10.1158/0008-5472.CAN-05-1622
• ⁴⁸
  Leung KC, Li MY, Leung BC, Hsin MK, Mok TS, Underwood MJ, et al. Thromboxane synthase suppression induces lung cancer cell apoptosis via inhibiting NF-κB. Exp Cell Res. 2010;316(20):3468-77, http://dx.doi.org/10.1016/j.yexcr.2010.07.003
  » http://dx.doi.org/10.1016/j.yexcr.2010.07.003
• ⁴⁹
  Giese A, Hagel C, Kim EL, Zapf S, Djawaheri J, Berens ME, et al. Thromboxane synthase regulates the migratory phenotype of human glioma cells. Neuro Oncol. 1999;1(1):3-13, http://dx.doi.org/10.1093/neuonc/1.1.3
  » http://dx.doi.org/10.1093/neuonc/1.1.3
• ⁵⁰
  Kürzel F, Hagel CH, Zapf S, Meissner H, Westphal M, Giese A. Cyclo oxygenase inhibitors and thromboxane synthase inhibitors differentially regulate migration arrest, growth inhibition and apoptosis in human glioma cells. Acta Neurochir (Wien). 2002;144(1):71-87.
• ⁵¹
  Schauff AK, Kim EL, Leppert J, Nadrowitz R, Wuestenberg R, Brockmann MA, et al. Inhibition of invasion-associated thromboxane synthase sensitizes experimental gliomas to gamma-radiation. J Neurooncol. 2009;91(3):241-9, http://dx.doi.org/10.1007/s11060-008-9708-0
  » http://dx.doi.org/10.1007/s11060-008-9708-0
• ⁵²
  Yoshizato K, Zapf S, Westphal M, Berens ME, Giese A. Thromboxane synthase inhibitors induce apoptosis in migration-arrested glioma cells. Neurosurgery.2002;50(2):343-54, http://dx.doi.org/10.1097/00006123-200202000-0002
  » http://dx.doi.org/10.1097/00006123-200202000-00021
• ⁵³
  Qualtrough D, Kaidi A, Chell S, Jabbour HN, Williams AC, Paraskeva C. Prostaglandin F(2alpha) stimulates motility and invasion in colorectal tumor cells. Int J Cancer. 2007;121(4):734-40, http://dx.doi.org/10.1002/ijc.22755
  » http://dx.doi.org/10.1002/ijc.22755
• ⁵⁴
  Sun SQ, Gu X, Gao XS, Li Y, Yu H, Xiong W, et al. Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to radiation. Oncotarget. 2016;7(30):48050-8.
• ⁵⁵
  Keightley MC, Sales KJ, Jabbour HN. PGF2α-F-prostanoid receptor signalling via ADAMTS1 modulates epithelial cell invasion and endothelial cell function in endometrial cancer. BMC Cancer. 2010;10:488, http://dx.doi.org/10.1186/1471-2407-10-488
  » http://dx.doi.org/10.1186/1471-2407-10-488
• ⁵⁶
  Sales KJ, Boddy SC, Jabbour HN. F-prostanoid receptor alters adhesion, morphology and migration of endometrial adenocarcinoma cells. Oncogene. 2008;27(17):2466-77, http://dx.doi.org/10.1038/sj.onc.1210883
  » http://dx.doi.org/10.1038/sj.onc.1210883
• ⁵⁷
  Müller K, Krieg P, Marks F, Fürstenberger G. Expression of PGF(2alpha) receptor mRNA in normal, hyperplastic and neoplastic skin. Carcinogenesis. 2000;21(5):1063-6, http://dx.doi.org/10.1093/carcin/21.5.1063
  » http://dx.doi.org/10.1093/carcin/21.5.1063
• ⁵⁸
  Scott G, Jacobs S, Leopardi S, Anthony FA, Learn D, Malaviya R, et al. Effects of PGF2alpha on human melanocytes and regulation of the FP receptor by ultraviolet radiation. Exp Cell Res. 2005;304(2):407-16, http://dx.doi.org/10.1016/j.yexcr.2004.11.016
  » http://dx.doi.org/10.1016/j.yexcr.2004.11.016
• ⁵⁹
  Vergote IB, Laekeman GM, Keersmaekers GH, Uyttenbroeck FL, Vanderheyden JS, Albertyn GP, et al. Prostaglandin F2 alpha in benign and malignant breast tumours. Br J Cancer. 1985;51(6):827-36, http://dx.doi.org/10.1038/bjc.1985.128
  » http://dx.doi.org/10.1038/bjc.1985.128
• ⁶⁰
  Watson J, Chuah SY. Prostaglandins, steroids and human mammary cancer. Eur J Cancer Clin Oncol. 1985;21(9):1051-5, http://dx.doi.org/10.1016/0277-5379(85)90290-1
  » http://dx.doi.org/10.1016/0277-5379(85)90290-1
• ⁶¹
  Cuneo KC, Fu A, Osusky KL, Geng L. Effects of vascular endothelial growth factor receptor inhibitor SU5416 and prostacyclin on murine lung metastasis. Anticancer Drugs. 2007;18(3):349-55, http://dx.doi.org/10.1097/CAD.0b013e328011fdab
  » http://dx.doi.org/10.1097/CAD.0b013e328011fdab
• ⁶²
  Keith RL, Miller YE, Hoshikawa Y, Moore MD, Gesell TL, Gao B, et al. Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Res. 2002;62(3):734-40.
• ⁶³
  Keith RL, Miller YE, Hudish TM, Girod CE, Sotto-Santiago S, Franklin WA, et al. Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice. Cancer Res. 2004;64(16):5897-904, http://dx.doi.org/10.1158/0008-5472.CAN-04-1070
  » http://dx.doi.org/10.1158/0008-5472.CAN-04-1070
• ⁶⁴
  McCormick DL, Spicer AM, Hollister JL. Differential effects of tranylcypromine and imidazole on mammary carcinogenesis in rats fed low and high fat diets. Cancer Res. 1989;49(12):3168-72.
• ⁶⁵
  Kreutzer M, Fauti T, Kaddatz K, Seifart C, Neubauer A, Schweer H, et al. Specific components of prostanoid-signaling pathways are present in non-small cell lung cancer cells. Oncol Rep. 2007;18(2):497-501.
• ⁶⁶
  Stearman RS, Dwyer-Nield L, Zerbe L, Blaine SA, Chan Z, Bunn PA Jr, et al. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol. 2005;167(6):1763-75, http://dx.doi.org/10.1016/S0002-9440(10)61257-6
  » http://dx.doi.org/10.1016/S0002-9440(10)61257-6
• ⁶⁷
  Camacho M, Piãeiro Z, Alcolea S, García J, Balart J, Terra X, et al. Prostacyclin-synthase expression in head and neck carcinoma patients and its prognostic value in the response to radiotherapy. J Pathol. 2015;235(1):125-35, http://dx.doi.org/10.1002/path.4453
  » http://dx.doi.org/10.1002/path.4453
• ⁶⁸
  Klein T, Benders J, Roth F, Baudler M, Siegle I, Kömhoff M. Expression of prostacyclin-synthase in human breast cancer: negative prognostic factor and protection against cell death in vitro. Mediators Inflamm. 2015;2015:864136.
• ⁶⁹
  Osawa T, Ohga N, Hida Y, Kitayama K, Akiyama K, Onodera Y, et al. Prostacyclin receptor in tumor endothelial cells promotes angiogenesis in an autocrine manner. Cancer Sci. 2012;103(6):1038-44, http://dx.doi.org/10.1111/j.1349-7006.2012.02261.x
  » http://dx.doi.org/10.1111/j.1349-7006.2012.02261.x
• ⁷⁰
  Murata T, Lin MI, Aritake K, Matsumoto S, Narumiya S, Ozaki H, et al. Role of prostaglandin D2 receptor DP as a suppressor of tumor hyperpermeability and angiogenesis in vivo. Proc Natl Acad Sci U S A. 2008;105(50):20009-14, http://dx.doi.org/10.1073/pnas.0805171105
  » http://dx.doi.org/10.1073/pnas.0805171105
• ⁷¹
  Fukushima M, Kato T, Ota K, Arai Y, Narumiya S, Hayaishi O. 9-deoxy delta 9-prostaglandin D2, a prostaglandin D2 derivative with potent antineoplastic and weak smooth muscle-contracting activities. Biochem Biophys Res Commun. 1982;109(3):626-33, http://dx.doi.org/10.1016/0006-291X(82)91986-6
  » http://dx.doi.org/10.1016/0006-291X(82)91986-6
• ⁷²
  Narumiya S, Ohno K, Fukushima M, Fujiwara M. Site and mechanism of growth inhibition by prostaglandins. III. Distribution and binding of prostaglandin A2 and delta 12-prostaglandin J2 in nuclei. J Pharmacol Exp Ther. 1987;242(1):306-11.
• ⁷³
  Stringfellow DA, Fitzpatrick FA. Prostaglandin D2 controls pulmonary metastasis of malignant melanoma cells. Nature. 1979;282(5734):76-8, http://dx.doi.org/10.1038/282076a0
  » http://dx.doi.org/10.1038/282076a0
• ⁷⁴
  Park JM, Kanaoka Y, Eguchi N, Aritake K, Grujic S, Materi AM, et al. Hematopoietic prostaglandin D synthase suppresses intestinal adenomas in ApcMin/+ mice. Cancer Res. 2007;67(3):881-9, http://dx.doi.org/doi: 10.1158/0008-5472.CAN-05-3767
  » http://dx.doi.org/10.1158/0008-5472.CAN-05-3767
• ⁷⁵
  Payne CA, Maleki S, Messina M, O’Sullivan MG, Stone G, Hall NR, et al. Loss of prostaglandin D2 synthase: a key molecular event in the transition of a low-grade astrocytoma to an anaplastic astrocytoma. Mol Cancer Ther. 2008;7(10):3420-8, http://dx.doi.org/10.1158/1535-7163.MCT-08-0629
  » http://dx.doi.org/10.1158/1535-7163.MCT-08-0629
• ⁷⁶
  Conde B, Tejedor M, Sinues E, Alcala A. Modulation of cell growth and differentiation induced by prostaglandin D2 in the glioma cell line C6. Anticancer Res. 1991;11(1):289-95.
• ⁷⁷
  Ferreira MT, Gomes RN, Panagopoulos AT, de Almeida FG, Veiga JC, Colquhoun A. Opposing roles of PGD(2) in GBM. Prostaglandins Other Lipid Mediat. 2018;134:66-76, http://dx.doi.org/10.1016/j.prostaglandins.2017.10.002
  » http://dx.doi.org/10.1016/j.prostaglandins.2017.10.002
• ⁷⁸
  Yoshida T, Ohki S, Kanazawa M, Mizunuma H, Kikuchi Y, Satoh H, et al. Inhibitory effects of prostaglandin D2 against the proliferation of human colon cancer cell lines and hepatic metastasis from colorectal cancer. Surg Today. 1998;28(7):740-5, http://dx.doi.org/10.1007/BF02484622
  » http://dx.doi.org/10.1007/BF02484622
• ⁷⁹
  Fukuoka T, Yashiro M, Kinoshita H, Morisaki T, Hasegawa T, Hirakawa T, et al. Prostaglandin D synthase is a potential novel therapeutic agent for the treatment of gastric carcinomas expressing PPARγ. Int J Cancer. 2015;137(5):1235-44, http://dx.doi.org/10.1002/ijc.29392
  » http://dx.doi.org/10.1002/ijc.29392
• ⁸⁰
  Azuma Y, Watanabe K, Date M, Daito M, Ohura K. Possible involvement of p38 in mechanisms underlying acceleration of proliferation by 15-deoxy-Delta(12,14)-prostaglandin J2 and the precursors in leukemia cell line THP-1. J Pharmacol Sci. 2004;94(3):261-70, http://dx.doi.org/10.1254/jphs.94.261
  » http://dx.doi.org/10.1254/jphs.94.261
• ⁸¹
  Chen YC, Shen SC, Tsai SH. Prostaglandin D(2) and J(2) induce apoptosis in human leukemia cells via activation of the caspase 3 cascade and production of reactive oxygen species. Biochim Biophys Acta. 2005;1743(3):291-304, http://dx.doi.org/10.1016/j.bbamcr.2004.10.016
  » http://dx.doi.org/10.1016/j.bbamcr.2004.10.016
• ⁸²
  Wang JJ, Mak OT. Induction of apoptosis in non-small cell lung carcinoma A549 cells by PGD2 metabolite, 15d-PGJ2. Cell Biol Int. 2011;35(11):1089-96, http://dx.doi.org/10.1042/CBI20100707
  » http://dx.doi.org/10.1042/CBI20100707
• ⁸³
  Smith WL, Murphy RC. The eicosanoids. cyclooxygenase, lipoxygenase, and epoxygenase pathways. In: Vance DE, Vance JE, editors. Biochemistry of lipids, lipoproteins and membranes. 4th ed. Amsterdam: Elsevier; 2002. p. 331-62.
• ⁸⁴
  Burnett BP, Levy RM. 5-Lipoxygenase metabolic contributions to NSAID-induced organ toxicity. Adv Ther. 2012;29(2):79-98, http://dx.doi.org/10.1007/s12325-011-0100-7
  » http://dx.doi.org/10.1007/s12325-011-0100-7
• ⁸⁵
  Powell WS, Rokach J. Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid. Biochim Biophys Acta. 2015;1851(4):340-55, http://dx.doi.org/10.1016/j.bbalip.2014.10.008
  » http://dx.doi.org/10.1016/j.bbalip.2014.10.008
• ⁸⁶
  Powell WS, Gravelle F, Gravel S. Metabolism of 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid and other 5(S)-hydroxyeicosanoids by a specific dehydrogenase in human polymorphonuclear leukocytes. J Biol Chem. 1992;267(27):19233-41.
• ⁸⁷
  Powell WS, Gravel S, MacLeod RJ, Mills E, Hashefi M. Stimulation of human neutrophils by 5-oxo-6,8,11,14-eicosatetraenoic acid by a mechanism independent of the leukotriene B4 receptor. J Biol Chem. 1993;268(13):9280-6.
• ⁸⁸
  Lepley RA, Muskardin DT, Fitzpatrick FA. Tyrosine kinase activity modulates catalysis and translocation of cellular 5-lipoxygenase. J Biol Chem. 1996;271(11):6179-84, http://dx.doi.org/10.1074/jbc.271.11.6179
  » http://dx.doi.org/10.1074/jbc.271.11.6179
• ⁸⁹
  Markoutsa S, Sürün D, Karas M, Hofmann B, Steinhilber D, Sorg BL. Analysis of 5-lipoxygenase phosphorylation on molecular level by MALDI-MS. FEBS J. 2014;281(8):1931-47, http://dx.doi.org/10.1111/febs.12759
  » http://dx.doi.org/10.1111/febs.12759
• ⁹⁰
  Werz O, Bürkert E, Fischer L, Szellas D, Dishart D, Samuelsson B, et al. Extracellular signal-regulated kinases phosphorylate 5-lipoxygenase and stimulate 5-lipoxygenase product formation in leukocytes. FASEB J. 2002;16(11):1441-3, http://dx.doi.org/10.1096/fj.01-0909fje
  » http://dx.doi.org/10.1096/fj.01-0909fje
• ⁹¹
  Werz O, Klemm J, Samuelsson B, Rådmark O. 5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases. Proc Natl Acad Sci U S A. 2000;97(10):5261-6, http://dx.doi.org/10.1073/pnas.050588997
  » http://dx.doi.org/10.1073/pnas.050588997
• ⁹²
  Werz O, Szellas D, Steinhilber D, Rådmark O. Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). J Biol Chem. 2002;277(17):14793-800, http://dx.doi.org/10.1074/jbc.M111945200
  » http://dx.doi.org/10.1074/jbc.M111945200
• ⁹³
  Luo M, Jones SM, Phare SM, Coffey MJ, Peters-Golden M, Brock TG. Protein kinase A inhibits leukotriene synthesis by phosphorylation of 5-lipoxygenase on serine 523. J Biol Chem. 2004;279(40):41512-20, http://dx.doi.org/10.1074/jbc.M312568200
  » http://dx.doi.org/10.1074/jbc.M312568200
• ⁹⁴
  Rådmark O, Samuelsson B. 5-lipoxygenase: regulation and possible involvement in atherosclerosis. Prostaglandins Other Lipid Mediat. 2007;83(3):162-74, http://dx.doi.org/10.1016/j.prostaglandins.2007.01.003
  » http://dx.doi.org/10.1016/j.prostaglandins.2007.01.003
• ⁹⁵
  Chari S, Clark-Loeser L, Shupack J, Washenik K. A role for leukotriene antagonists in atopic dermatitis? Am J Clin Dermatol. 2001;2(1):1-6, http://dx.doi.org/10.2165/00128071-200102010-00001
  » http://dx.doi.org/10.2165/00128071-200102010-00001
• ⁹⁶
  Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med. 2007;357(18):1841-54, http://dx.doi.org/10.1056/NEJMra071371
  » http://dx.doi.org/10.1056/NEJMra071371
• ⁹⁷
  Ghosh J, Myers CE. Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Natl Acad Sci U S A. 1998;95(22):13182-7, http://dx.doi.org/10.1073/pnas.95.22.13182
  » http://dx.doi.org/10.1073/pnas.95.22.13182
• ⁹⁸
  Larré S, Tran N, Fan C, Hamadeh H, Champigneulles J, Azzouzi R, et al. PGE2 and LTB4 tissue levels in benign and cancerous prostates. Prostaglandins Other Lipid Mediat. 2008;87(1-4):14-9, http://dx.doi.org/10.1016/j.prostaglandins.2008.05.001
  » http://dx.doi.org/10.1016/j.prostaglandins.2008.05.001
• ⁹⁹
  Ishii K, Zaitsu M, Yonemitsu N, Kan Y, Hamasaki Y, Matsuo M. 5-lipoxygenase pathway promotes cell proliferation in human glioma cell lines. Clin Neuropathol. 2009;28(6):445-52, http://dx.doi.org/10.5414/NPP28445
  » http://dx.doi.org/10.5414/NPP28445
• ¹⁰⁰
  Wasilewicz MP, Kołodziej B, Bojułko T, Kaczmarczyk M, Sulzyc-Bielicka V, Bielicki D, et al. Overexpression of 5-lipoxygenase in sporadic colonic adenomas and a possible new aspect of colon carcinogenesis. Int J Colorectal Dis. 2010;25(9):1079-85, http://dx.doi.org/10.1007/s00384-010-0980-z
  » http://dx.doi.org/10.1007/s00384-010-0980-z
• ¹⁰¹
  Hennig R, Ding XZ, Tong WG, Schneider MB, Standop J, Friess H, et al. 5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am J Pathol. 2002;161(2):421-8, http://dx.doi.org/10.1016/S0002-9440(10)64198-3
  » http://dx.doi.org/10.1016/S0002-9440(10)64198-3
• ¹⁰²
  Ihara A, Wada K, Yoneda M, Fujisawa N, Takahashi H, Nakajima A. Blockade of leukotriene B4 signaling pathway induces apoptosis and suppresses cell proliferation in colon cancer. J Pharmacol Sci. 2007;103(1):24-32, http://dx.doi.org/10.1254/jphs.FP0060651
  » http://dx.doi.org/10.1254/jphs.FP0060651
• ¹⁰³
  Moore GY, Pidgeon GP. Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway. Int J Mol Sci. 2017;18(2): E236, http://dx.doi.org/10.3390/ijms18020236
  » http://dx.doi.org/10.3390/ijms18020236
• ¹⁰⁴
  Cheon EC, Khazaie K, Khan MW, Strouch MJ, Krantz SB, Phillips J, et al. Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APCDelta468 mice. Cancer Res. 2011;71(5):1627-36, http://dx.doi.org/10.1158/0008-5472.CAN-10-1923
  » http://dx.doi.org/10.1158/0008-5472.CAN-10-1923
• ¹⁰⁵
  Poczobutt JM, Nguyen TT, Hanson D, Li H, Sippel TR, Weiser-Evans MC, et al. Deletion of 5-Lipoxygenase in the Tumor Microenvironment Promotes Lung Cancer Progression and Metastasis through Regulating T Cell Recruitment. J Immunol. 2016;196(2):891-901, http://dx.doi.org/10.4049/jimmunol.1501648
  » http://dx.doi.org/10.4049/jimmunol.1501648
• ¹⁰⁶
  Goetzl EJ, Brash AR, Tauber AI, Oates JA, Hubbard WC. Modulation of human neutrophil function by monohydroxy-eicosatetraenoic acids. Immunology. 1980;39(4):491-501.
• ¹⁰⁷
  Miller AW, Katakam PV, Lee HC, Tulbert CD, Busija DW, Weintraub NL. Arachidonic acid-induced vasodilation of rat small mesenteric arteries is lipoxygenase-dependent. J Pharmacol Exp Ther. 2003;304(1):139-44, http://dx.doi.org/10.1124/jpet.102.041780
  » http://dx.doi.org/10.1124/jpet.102.041780
• ¹⁰⁸
  Aharony D, Smith JB, Silver MJ. Regulation of arachidonate-induced platelet aggregation by the lipoxygenase product, 12-hydroperoxyeicosatetraenoic acid. Biochim Biophys Acta. 1982;718(2):193-200, http://dx.doi.org/10.1016/0304-4165(82)90219-7
  » http://dx.doi.org/10.1016/0304-4165(82)90219-7
• ¹⁰⁹
  Takenaga M, Hirai A, Terano T, Tamura Y, Kitagawa H, Yoshida S. Comparison of the in vitro effect of eicosapentaenoic acid (EPA)-derived lipoxygenase metabolites on human platelet function with those of arachidonic acid. Thromb Res. 1986;41(3):373-84, http://dx.doi.org/10.1016/0049-3848(86)90248-3
  » http://dx.doi.org/10.1016/0049-3848(86)90248-3
• ¹¹⁰
  Sekiya F, Takagi J, Usui T, Kawajiri K, Kobayashi Y, Sato F, et al. 12S-hydroxyeicosatetraenoic acid plays a central role in the regulation of platelet activation. Biochem Biophys Res Commun. 1991;179(1):345-51, http://dx.doi.org/10.1016/0006-291X(91)91376-N
  » http://dx.doi.org/10.1016/0006-291X(91)91376-N
• ¹¹¹
  Gao X, Grignon DJ, Chbihi T, Zacharek A, Chen YQ, Sakr W, et al. Elevated 12-lipoxygenase mRNA expression correlates with advanced stage and poor differentiation of human prostate cancer. Urology. 1995;46(2):227-37, http://dx.doi.org/10.1016/S0090-4295(99)80198-8
  » http://dx.doi.org/10.1016/S0090-4295(99)80198-8
• ¹¹²
  Guo Y, Zhang W, Giroux C, Cai Y, Ekambaram P, Dilly AK, et al. Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid. J Biol Chem. 2011;286(39):33832-40, http://dx.doi.org/10.1074/jbc.M110.216564
  » http://dx.doi.org/10.1074/jbc.M110.216564
• ¹¹³
  Szekeres CK, Trikha M, Nie D, Honn KV. Eicosanoid 12(S)-HETE activates phosphatidylinositol 3-kinase. Biochem Biophys Res Commun. 2000;275(2):690-5, http://dx.doi.org/10.1006/bbrc.2000.3348
  » http://dx.doi.org/10.1006/bbrc.2000.3348
• ¹¹⁴
  Vonach C, Viola K, Giessrigl B, Huttary N, Raab I, Kalt R, et al. NF-κB mediates the 12(S)-HETE-induced endothelial to mesenchymal transition of lymphendothelial cells during the intravasation of breast carcinoma cells. Br J Cancer. 2011;105(2):263-71, http://dx.doi.org/10.1038/bjc.2011.194
  » http://dx.doi.org/10.1038/bjc.2011.194
• ¹¹⁵
  Rigby DA, Ferguson DJ, Johnson LA, Jackson DG. Neutrophils rapidly transit inflamed lymphatic vessel endothelium via integrin-dependent proteolysis and lipoxin-induced junctional retraction. J Leukoc Biol. 2015;98(6):897-912, http://dx.doi.org/10.1189/jlb.1HI0415-149R
  » http://dx.doi.org/10.1189/jlb.1HI0415-149R
• ¹¹⁶
  Wculek SK, Malanchi I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature. 2015;528(7582):413-7, http://dx.doi.org/10.1038/nature16140
  » http://dx.doi.org/10.1038/nature16140
• ¹¹⁷
  Nguyen CH, Stadler S, Brenner S, Huttary N, Krieger S, Jäger W, et al. Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching. Br J Cancer. 2016;115(3):364-70, http://dx.doi.org/10.1038/bjc.2016.201
  » http://dx.doi.org/10.1038/bjc.2016.201
• ¹¹⁸
  Chen YQ, Duniec ZM, Liu B, Hagmann W, Gao X, Shimoji K, et al. Endogenous 12(S)-HETE production by tumor cells and its role in metastasis. Cancer Res. 1994;54(6):1574-9.
• ¹¹⁹
  Nie D, Tang K, Diglio C, Honn KV. Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase. Blood. 2000;95(7):2304-11.
• ¹²⁰
  Wong BC, Wang WP, Cho CH, Fan XM, Lin MC, Kung HF, et al. 12-Lipoxygenase inhibition induced apoptosis in human gastric cancer cells. Carcinogenesis. 2001;22(9):1349-54, http://dx.doi.org/10.1093/carcin/22.9.1349
  » http://dx.doi.org/10.1093/carcin/22.9.1349
• ¹²¹
  Klampfl T, Bogner E, Bednar W, Mager L, Massudom D, Kalny I, et al. Up-regulation of 12(S)-lipoxygenase induces a migratory phenotype in colorectal cancer cells. Exp Cell Res. 2012;318(6):768-78, http://dx.doi.org/10.1016/j.yexcr.2011.12.017
  » http://dx.doi.org/10.1016/j.yexcr.2011.12.017
• ¹²²
  Kerjaschki D, Bago-Horvath Z, Rudas M, Sexl V, Schneckenleithner C, Wolbank S, et al. Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. J Clin Invest. 2011;121(5):2000-12, http://dx.doi.org/10.1172/JCI44751
  » http://dx.doi.org/10.1172/JCI44751
• ¹²³
  Nguyen CH, Brenner S, Huttary N, Li Y, Atanasov AG, Dirsch VM, et al. 12(S)-HETE increases intracellular Ca(2+) in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply. Cancer Lett. 2016;380(1):174-83, http://dx.doi.org/10.1016/j.canlet.2016.06.022
  » http://dx.doi.org/10.1016/j.canlet.2016.06.022
• ¹²⁴
  Kuhn H, Walther M, Kuban RJ. Mammalian arachidonate 15-lipoxygenases structure, function, and biological implications. Prostaglandins Other Lipid Mediat. 2002;68-69:263-90, http://dx.doi.org/10.1016/S0090-6980(02)00035-7
  » http://dx.doi.org/10.1016/S0090-6980(02)00035-7
• ¹²⁵
  Conrad DJ. The arachidonate 12/15 lipoxygenases. A review of tissue expression and biologic function. Clin Rev Allergy Immunol. 1999;17(1-2):71-89, http://dx.doi.org/10.1007/BF02737598
  » http://dx.doi.org/10.1007/BF02737598
• ¹²⁶
  Brash AR, Boeglin WE, Chang MS. Discovery of a second 15S-lipoxygenase in humans. Proc Natl Acad Sci U S A. 1997;94(12):6148-52, http://dx.doi.org/10.1073/pnas.94.12.6148
  » http://dx.doi.org/10.1073/pnas.94.12.6148
• ¹²⁷
  Wecksler AT, Kenyon V, Deschamps JD, Holman TR. Substrate specificity changes for human reticulocyte and epithelial 15-lipoxygenases reveal allosteric product regulation. Biochemistry. 2008;47(28):7364-75, http://dx.doi.org/10.1021/bi800550n
  » http://dx.doi.org/10.1021/bi800550n
• ¹²⁸
  Wittwer J, Hersberger M. The two faces of the 15-lipoxygenase in atherosclerosis. Prostaglandins Leukot Essent Fatty Acids. 2007;77(2):67-77, http://dx.doi.org/10.1016/j.plefa.2007.08.001
  » http://dx.doi.org/10.1016/j.plefa.2007.08.001
• ¹²⁹
  Andersson CK, Claesson HE, Rydell-Törmänen K, Swedmark S, Hällgren A, Erjefält JS. Mice lacking 12/15-lipoxygenase have attenuated airway allergic inflammation and remodeling. Am J Respir Cell Mol Biol. 2008;39(6):648-56, http://dx.doi.org/10.1165/rcmb.2007-0443OC
  » http://dx.doi.org/10.1165/rcmb.2007-0443OC
• ¹³⁰
  Chakrabarti SK, Cole BK, Wen Y, Keller SR, Nadler JL. 12/15-lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes. Obesity (Silver Spring). 2009;17(9):1657-63, http://dx.doi.org/10.1038/oby.2009.192
  » http://dx.doi.org/10.1038/oby.2009.192
• ¹³¹
  Serhan CN, Jain A, Marleau S, Clish C, Kantarci A, Behbehani B, et al. Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J Immunol. 2003;171(12):6856-65, http://dx.doi.org/10.4049/jimmunol.171.12.6856
  » http://dx.doi.org/10.4049/jimmunol.171.12.6856
• ¹³²
  Emerson MR, LeVine SM. Experimental allergic encephalomyelitis is exacerbated in mice deficient for 12/15-lipoxygenase or 5-lipoxygenase. Brain Res. 2004;1021(1):140-5, http://dx.doi.org/10.1016/j.brainres.2004.06.045
  » http://dx.doi.org/10.1016/j.brainres.2004.06.045
• ¹³³
  Merched AJ, Ko K, Gotlinger KH, Serhan CN, Chan L. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J. 2008;22(10):3595-606, http://dx.doi.org/10.1096/fj.08-112201
  » http://dx.doi.org/10.1096/fj.08-112201
• ¹³⁴
  Habouri L, El Mansouri FE, Ouhaddi Y, Lussier B, Pelletier JP, Martel-Pelletier J, et al. Deletion of 12/15 lipoxygenase accelerates the development of aging-associated and instability-induced osteoarthritis. Osteoarthritis Cartilage. 2017;25(10):1719-28, http://dx.doi.org/10.1016/j.joca.2017.07.001
  » http://dx.doi.org/10.1016/j.joca.2017.07.001
• ¹³⁵
  Zhang B, Cao H, Rao GN. 15(S)-hydroxyeicosatetraenoic acid induces angiogenesis via activation of PI3K-Akt-mTOR-S6K1 signaling. Cancer Res. 2005;65(16):7283-91, http://dx.doi.org/10.1158/0008-5472.CAN-05-0633
  » http://dx.doi.org/10.1158/0008-5472.CAN-05-0633
• ¹³⁶
  Wang D, Liu Y, Chen L, Li P, Qu Y, Zhu Y, et al. Key role of 15-LO/15-HETE in angiogenesis and functional recovery in later stages of post-stroke mice. Sci Rep. 2017;7:46698, http://dx.doi.org/10.1038/srep46698
  » http://dx.doi.org/10.1038/srep46698
• ¹³⁷
  Hayashi T, Noshita N, Sugawara T, Chan PH. Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab. 2003;23(2):166-80, http://dx.doi.org/10.1097/01.WCB.0000041283.53351.CB
  » http://dx.doi.org/10.1097/01.WCB.0000041283.53351.CB
• ¹³⁸
  Jiang Q, Zhang ZG, Ding GL, Zhang L, Ewing JR, Wang L, et al. Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI. Neuroimage. 2005;28(3):698-707, http://dx.doi.org/10.1016/j.neuroimage.2005.06.063
  » http://dx.doi.org/10.1016/j.neuroimage.2005.06.063
• ¹³⁹
  Slevin M, Kumar P, Gaffney J, Kumar S, Krupinski J. Can angiogenesis be exploited to improve stroke outcome? Mechanisms and therapeutic potential. Clin Sci (Lond). 2006;111(3):171-83.
• ¹⁴⁰
  Shureiqi I, Chen D, Lee JJ, Yang P, Newman RA, Brenner DE, et al. 15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells. J Natl Cancer Inst. 2000;92(14):1136-42, http://dx.doi.org/10.1093/jnci/92.14.1136
  » http://dx.doi.org/10.1093/jnci/92.14.1136
• ¹⁴¹
  Shureiqi I, Jiang W, Zuo X, Wu Y, Stimmel JB, Leesnitzer LM, et al. The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-delta to induce apoptosis in colorectal cancer cells. Proc Natl Acad Sci U S A. 2003;100(17):9968-73, http://dx.doi.org/10.1073/pnas.1631086100
  » http://dx.doi.org/10.1073/pnas.1631086100
• ¹⁴²
  Cimen I, Tunçay S, Banerjee S. 15-Lipoxygenase-1 expression suppresses the invasive properties of colorectal carcinoma cell lines HCT-116 and HT-29. Cancer Sci. 2009;100(12):2283-91, http://dx.doi.org/10.1111/j.1349-7006.2009.01313.x
  » http://dx.doi.org/10.1111/j.1349-7006.2009.01313.x
• ¹⁴³
  Jiang WG, Watkins G, Douglas-Jones A, Mansel RE. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins Leukot Essent Fatty Acids. 2006;74(4):235-45, http://dx.doi.org/10.1016/j.plefa.2006.01.009
  » http://dx.doi.org/10.1016/j.plefa.2006.01.009
• ¹⁴⁴
  Hennig R, Kehl T, Noor S, Ding XZ, Rao SM, Bergmann F, et al. 15-lipoxygenase-1 production is lost in pancreatic cancer and overexpression of the gene inhibits tumor cell growth. Neoplasia. 2007;9(11):917-26, http://dx.doi.org/10.1593/neo.07565
  » http://dx.doi.org/10.1593/neo.07565
• ¹⁴⁵
  Tavakoli Yaraki M, Karami Tehrani F. Apoptosis Induced by 13-S-hydroxyoctadecadienoic acid in the Breast Cancer Cell Lines, MCF-7 and MDA-MB-231. Iran J Basic Med Sci. 2013;16(4):653-9.
• ¹⁴⁶
  Hsi LC, Wilson LC, Eling TE. Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor gamma. J Biol Chem. 2002;277(43):40549-56, http://dx.doi.org/10.1074/jbc.M203522200
  » http://dx.doi.org/10.1074/jbc.M203522200
• ¹⁴⁷
  Kelavkar UP, Cohen C, Kamitani H, Eling TE, Badr KF. Concordant induction of 15-lipoxygenase-1 and mutant p53 expression in human prostate adenocarcinoma: correlation with Gleason staging. Carcinogenesis. 2000;21(10):1777-87, http://dx.doi.org/10.1093/carcin/21.10.1777
  » http://dx.doi.org/10.1093/carcin/21.10.1777
• ¹⁴⁸
  Sen M, McHugh K, Hutzley J, Philips BJ, Dhir R, Parwani AV, et al. Orthotopic expression of human 15-lipoxygenase (LO)-1 in the dorsolateral prostate of normal wild-type C57BL/6 mouse causes PIN-like lesions. Prostaglandins Other Lipid Mediat. 2006;81(1-2):1-13, http://dx.doi.org/10.1016/j.prostaglandins.2006.05.024
  » http://dx.doi.org/10.1016/j.prostaglandins.2006.05.024
• ¹⁴⁹
  Chang J, Jiang L, Wang Y, Yao B, Yang S, Zhang B, et al. 12/15 Lipoxygenase regulation of colorectal tumorigenesis is determined by the relative tumor levels of its metabolite 12-HETE and 13-HODE in animal models. Oncotarget. 2015;6(5):2879-88, http://dx.doi.org/10.18632/oncotarget.2994
  » http://dx.doi.org/10.18632/oncotarget.2994
• ¹⁵⁰
  Nony PA, Kennett SB, Glasgow WC, Olden K, Roberts JD. 15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. J Biol Chem. 2005;280(36):31413-9, http://dx.doi.org/10.1074/jbc.M500418200
  » http://dx.doi.org/10.1074/jbc.M500418200
• ¹⁵¹
  Li MY, Yuan HL, Ko FW, Wu B, Long X, Du J, et al. Antineoplastic effects of 15(S)-hydroxyeicosatetraenoic acid and 13-S-hydroxyoctadecadienoic acid in non-small cell lung cancer. Cancer. 2015;121 Suppl 17:3130-45, http://dx.doi.org/10.1002/cncr.29547
  » http://dx.doi.org/10.1002/cncr.29547
• ¹⁵²
  Jack GS, Brash AR, Olson SJ, Manning S, Coffey CS, Smith JA Jr, et al. Reduced 15-lipoxygenase-2 immunostaining in prostate adenocarcinoma: correlation with grade and expression in high-grade prostatic intraepithelial neoplasia. Hum Pathol. 2000; 31(9):1146-54, http://dx.doi.org/10.1053/hupa.2000.16670
  » http://dx.doi.org/10.1053/hupa.2000.16670

Publication Dates

• Publication in this collection
  2018

History

• Received
  3 Jan 2018
• Accepted
  5 Mar 2018