Eicosanoids in prostate cancer
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Many epidemiological studies revealed an association of dietary consumption of fatty acids and prostate cancer. Linoleic acid and alpha-linolenic acid and their derivatives such as arachidonic acid and eicosapentanoic acid are important polyunsaturated fatty acids in animal fats and in many vegetable oils. Their metabolism at the cellular level by enzymes such as lipoxygenases and cycloxygenases produces the group of eicosanoids molecules with many biological roles and activities in a variety of human diseases including cancer. In this review, we describe the biological activities of lipids with focus in eicosanoids and prostate cancer.
KeywordsPolyunsaturated fatty acids (PUFAs) Arachidonic acid Lipoxygenases Prostaglandins Hydroxyeicosatetraenoic acids (HETEs) 5-oxo-eicosatetraenoic acid (5-oxo-ETE)
Prostate cancer being the most common cancer and the first death cause in men has been extensively studied during the last decades, with great improvement in diagnosis and treatment approaches . However, our knowledge on causative and progression factors is still rather limited. In fact, there is great need, to recognize factors that influence progression to a more aggressive/metastatic state, so that among men that are diagnosed at an early stage of the disease, populations at high risk could be identified and treated and/or advised appropriately. A large number of evidence from epidemiological as well as in vitro and in vivo studies have revealed an association of fatty acids and their metabolites with cancer incidence and mortality. In the present review, we will try to summarize the current knowledge on eicosanoids’ (metabolites of polyunsaturated fatty acids, PUFAs, such as arachidonic acid) influence on prostate cancer.
The term eicosanoids is used to describe a diverse group of PUFAs of 20 carbon units in length that includes arachidonic acid (an ω-6 fatty acid) and other similar PUFAs such as adrenic and dihomo-gamma-linolenic acid (ω-6 fatty acids), eicosapentaenoic (an ω-3 fatty acid) and mead acid (an ω-9 fatty acid), and their metabolites. The latter are important signaling molecules with an autocrine, paracrine, and endocrine action, involved in the function of different systems and organs such as immune, reproductive, gastrointestinal, and kidneys, regulating several physiological and pathological processes, such as cell growth, inflammation, allergy, pain perception, and blood pressure. The first step in arachidonic acid metabolism requires its release from cell membrane phospholipids, under the action of phospholipase A2 (PLA2), a process initiated by several stimuli like ischemia, mechanical trauma, hormones, growth factors, and cytokines. Subsequently, oxidation of arachidonic acid by different enzymes, such as cyclooxygenases (COXs), lipoxygenases (LOXs) cytochrome P450 epoxygenases (EPXs), or hydroxylases, leads to the production of the different eicosanoid molecules. Two major groups of eicosanoids have been described. The first one includes the so called classic eicosanoids like hydroxyeicosatetraenoic acids (HETEs), leukotrienes (LKs), eoxins (EXs), resolvins (RvEs), hydroxy-eicosapentaenoic acids (HEPEs) and prostanoids like prostaglandins (PGs), prostacyclins (PCs), and thromboxanes (TXs). The second one with the non-classic eicosanoids comprises of oxo-eicosanoids (oxo-ETEs), hepoxillins (Hxs), lipoxins (Lxs), epilipoxins (Epi-Lxs) epoxyeicosatrienoic acids (EETs), epoxyeicosatetranoic acids (EEQs), and isoprostanes (isoPs).
3 Sources of fatty acids
Arachidonic acid (AA, 20:4n-6) is the most abundant ω-6 fatty acid incorporated in cell membranes, along with the ω-3 series fatty acids such as eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). They are derivatives of linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (α-LNA, 18:3n-3) respectively. They are essential fatty acids which they cannot be synthesized de novo and must be taken from the diet. Linoleic acid is abundant in vegetable oils while α-linolenic acid is found at moderate levels in most plants; its main source in the human diet is fish or fish oil. Therefore, their levels and subsequently the levels of their derivatives within the organism depend primarily on dietary intake and on the activity of the enzymes involved in their metabolism and biotransformation . In fact, gene polymorphism of the various fatty acid metabolizing enzymes accounts for differences in fatty acid metabolism among individuals .
3.2 De novo
Cancer cells exhibit an altered metabolism, to cope with their increased proliferation rate. Alterations involve high glucose consumption for their energy needs and new molecules synthesis through their modified anabolic processes . Indeed, there is a high demand for fatty acids, which apart from being building blocks in cell membranes can also be used to produce energy, modify proteins through lipoylation, and act as signaling molecules. Hence, under normal conditions, the production of fatty acids in cells other than adipose and lung tissue, brain, and liver, is relatively small, while in cancer, including prostate cancer, increased de novo production of fatty acids occurs along with a high dependence of cancer cells on exogenous fatty acid uptake and consumption, the latter through fatty acid β-oxidation (FAO) pathway .
Even though ω-3 and ω-6 series PUFAS cannot be synthesized de novo, there is an interconnection of de novo fatty acid synthesis with eicosanoids biosynthesis since malonyl-CoA that is produced by acetyl-CoA is also required for PUFA elongation to longer chain species. The key enzyme in de novo fatty acid synthesis is fatty acid synthase. Overexpression of the fatty acid synthase gene which is a common phenomenon in prostate tumors directly related to Akt/PKB activation, in combination with increased stabilization of fatty acid synthase by ubiquitin-specific protease-2a (USP2a) results in increased de novo fatty acid synthesis [56, 61]. Equally, overexpression of the sterol response element-binding protein-1c (SREBP-1c) that regulates the enzymes involved in this process leads to tumor growth in prostate and migration of cancer cells to distant organs [2, 17].
4 Role of fatty acid intake and metabolism in prostate cancer
4.1 Epidemiological evidence
First evidence for the existence of an association of lipid consumption and prostate cancer came from the observations that prostate cancer mortality rates are especially high in Northern Europe and America and much lower in Asian countries and that immigrates from Asia in America have an increased risk of developing prostate cancer. This suggests that dietary factors may account for this difference, since western diet, in contrast to eastern diet, contains higher levels of saturated fats . However, epidemiological findings concerning the association of n-3 and n-6 PUFAS that are substrates for eicosanoid synthesis and prostate cancer risk are inconclusive. Several studies have reported that a high intake of PUFAS is either positively or weakly associated with prostate cancer along with a significant positive association between arachidonic acid and its metabolites in serum , while an inverse association was reported for n-3 PUFAS since their levels were found decreased in patients with benign prostatic hyperplasia and prostate cancer . Indeed, a meta-analysis and an observational study, comparing high and low intake of alpha-linolenic acid found a small (significant) decrease in the risk for prostate cancer [10, 45]. This difference was explained by the fact that n-6 PUFAS are converted predominately into pro-inflammatory eicosanoids, while n-3 PUFAs are converted into anti-inflammatory or less pro-inflammatory eicosanoids . Higher levels of n-6 and n-3 PUFAS (except EPA) in diet, as depicted in their higher distribution in red blood cells may be associated with higher-grade prostate cancer . On the other hand, in several meta-analysis studies, no association for dietary intake was observed, but higher levels of alpha-linolenic acid in blood and adipose tissue were associated with increased risk of prostate cancer [7, 11, 52].
Inconclusive were also the findings from the alpha omega trial (a double-blind placebo-controlled trial of alpha-linolenic acid and the fish fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) on the recurrence of cardiovascular disease) in which PSA levels were measured initially and after consuming 2 g per day of alpha-linolenic acid for 40 months. A small but not significant increase in PSA was observed compared to the placebo group .
4.2 Changes in the biosynthesis of eicosanoids
As mentioned above, the first step for fatty acids metabolism is their release from phospholipids by the action of phospholipase A2 (PLA2) enzymes. Four major types of PLA2 enzymes (secretory sPLA2s; cytosolic cPLA2s and calcium-independent iPLA2s; acetyl hydrolase/oxidized lipid lipoprotein associated (Lp)PLA2s) have been identified with different selectivity for phospholipids with ω6 and ω3 PUFA . Therefore, the release of fatty acids from phospholipids can be quite different between ω6 and ω3 PUFA, depending on the relative expression of the various phospholipases. Interestingly, in prostate cancer, it has been found that sPLA2 was upregulated, while inhibitors of cPLA2 were downregulated  indicating a possible increased release of ω6 PUFA, since ω3 PUFA (EPA or DHA) are poor substrates for cPLA2 [36, 46]. Additionally, the levels of sPLA2 were found to be increased in high Gleason grade prostate carcinomas and correlated with increased cell proliferation. Elevated activity of iPLA 2 has been also associated with malignant prostate tumor cells and prostate cancer cell growth .
After the release of fatty acids, COXs and LOXs are the main enzymes in the production of the different eicosanoids. They exist in different isoforms and their altered expression levels in cancer, including prostate cancer, have been extensively studied.
It has been found that COX-2 isoform is mainly expressed under the influence of certain stimuli, such as TNFα and that prostate cancer tumors express higher levels of COX-2 in relation to normal tissues and to the expression of COX-1. However, findings on COX-1 levels in prostate cancer cells compared to normal ones are rather contradictory. Uotila et al. showed that there was no difference in COX-1 expression between carcinoma and normal prostate samples , while Kirschenbaum et al. reported an upregulated expression of COX-1 in luminal epithelial prostate cancer cells . Moreover, COX-2-enhanced expression by TNFα treatment was also found to be differentially distributed within normal (perinuclear) and prostate cancer cells (cytoplasmic) . Increased COX-2 expression was also found after prostaglandin treatment of PC-3 and LNCaP cells for 4 days .
Similarly, differences in LOXs expression between cancerous and benign tumors or normal prostate tissue was investigated. Overexpression of 5-LOX in prostate cancer tissue specimens was first described by Gupta and his colleagues . Overexpression of 5-LOX was further verified by findings of increased production of 5-HETE in malignant tumors. Similarly, 12-LOX was overexpressed in prostate cancer and was strongly associated with poor differentiation and invasiveness , since 12-LOX expression seems to stimulate angiogenesis . Furthermore, it has been shown that leukotriene B4 (LTB4) levels were increased in prostate cancers . On the other hand, a reduction on 15-Lox-2 and its product 15-HETE has been reported in prostate cancer compared to normal human prostate cells and suggested as a negative cell cycle regulator in normal human prostate epithelial cells [5, 51].
A rather interesting finding was that LOX products may exert a negative feedback on COX-1 gene expression in prostate cancer cells, as was revealed by cPLA(2) alpha inhibition that induced the expression of COX-1 and increased PGE2 levels and decreased most LOX products (HETEs), while replenishing 5- and 12-HETEs abolished this effect . Moreover, prostate carcinomas have been also characterized by high thromboxane synthases levels compared to normal tissue and associated with advanced and high-grade disease [16, 64].
5 Eicosanoid effects on prostate cancer cells
Several experimental studies point out the significant action of eicosanoids on prostate cancer cells, affecting important cellular processes like cell proliferation, apoptosis, angiogenesis, and metastasis. However, their effects are rather heterogeneous. It has been found that, while n-3 PUFAS derived from alpha-linolenic acid such as EPA and DHA and their metabolites suppress prostate cancer cell growth, n-6 PUFAS such as arachidonic acid from linoleic acid promote prostate tumors. More specifically, linoleic acid and arachidonic acid have been shown to promote cell proliferation of prostate cancer cells both in vitro and in vivo [4, 12, 44, 48], while in tumor specimens from radical prostatectomy, arachidonic acid levels were low, due to increased metabolism, supported by increased amounts of PGE2 . Indeed, PGE2 has been reported to promote carcinogenesis by modulating proliferation, apoptosis, migration and invasion, while inhibition of its production with cyclooxygenase inhibitors has the opposite effects [1, 12, 49]. The later led to an increased interest in utilizing such inhibitors/antagonists (old ones like NSAIDS or newly identified molecules) for therapeutic use [21, 49]. Indeed, an inhibitory effect on prostate cancer cell proliferation was observed by two COX-2 inhibitors, CAY10404 and celecoxib . The latter was also tested in the multi-arm randomized controlled STAMPEDE trial, which failed to show a benefit in men with locally advanced or metastatic prostate cancer, under androgen deprivation therapy . In a prostate-specific Pten knockout and omega-3 desaturase transgenic mouse model, COX-1, COX-2, and LOX-5 were further proved to promote tumor growth, while COX-1 was required for the protective effects of ω-3 PUFA, suggesting that ω-3 metabolites of COX-1 could suppress cancer growth . Moreover, PGE2 has been reported to mediate the TGF-beta effects on prostate cancer cell migration and invasion in PC3 cells via activation of the PI3K/AKT/mTOR pathway .
Ghosh and his colleagues found a stimulatory effect of arachidonic acid on the proliferation of PC3 and LNCaP prostate cancer cells, an effect reverted by inhibitors of 5-LOX [23, 24], but not by COX inhibitors. This stimulatory effect was only mimicked by 5-oxo-ETE, while other 5-LOX metabolites such as leukotrienes were ineffective . The effect of 5-oxo-ETE is mediated by OXER1 which has been identified in different cancers including prostate. Reduced expression of OXER1 was found to result in reduced cell viability of PC3 cells, pointing out the importance of this receptor and its endogenously produced ligand 5-oxo-ETE in the survival of prostate cancer cells [25, 42, 55]. This is quite important, since 5-oxo-ETE synthesis could be triggered by 5-HETE production by immune cells in the tumor microenvironment, such as neutrophils that exhibit high 5-LOX activity, as demonstrated by Grant and his colleagues . Furthermore, we have recently shown that this receptor can act as a membrane-located receptor for androgens , having an antagonistic action, mediating testosterone’s previously described apoptotic, and antimigratory effects [15, 30, 31]. The precursor of 5-oxo-ETE, 5-HETE has also been suggested to promote survival of human prostate cancer cells . Increased apoptosis of prostate cancer cells was also reported by Sarveswaran and his colleagues by MK591, a specific inhibitor of 5-LOX activity, that is, mediated via down-regulation of protein kinase C-epsilon . 12(S) HETE, another arachidonic acid metabolite produced by LOX enzymes, has been reported to induce angiogenesis by stimulating VEGF expression in prostate cancer cells [37, 40].
As already mentioned, certain eicosanoid metabolites may function as tumor suppressors. This group includes EPA and DHA, derived from alpha-linolenic acid , which have been described to decrease the growth of LNCaP cells with a decreased expression of the androgen receptor and a suppressed Akt/mTOR signaling pathway . EPA also inhibits voltage-gated sodium channels and invasiveness of PC3 prostate cancer cells . Equally, the 15-LOX product, 15-HETE and 15-deoxy-Δ12,14-PGJ2, the metabolite of PGJ2, has been shown to suppress prostate cancer cell growth [58, 62] with the later acting as a potent AR inhibitor [28, 39].
6 Concluding remarks
All the above presented data provide a substantial amount of evidence that eicosanoids have a significant role in prostate cancer. Their levels in the blood and prostate tissue not only as a result of dietary intake and biotransformation but also due to their production by immune cells in the tumor microenvironment should be definitely taken into account and further explored. This will increase our knowledge on the mechanisms involved and will possibly provide new prevention and/or therapeutic strategies for prostate cancer.
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