Biochimie 107 (2014) 114e123

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Secreted phospholipases A2 in cancer: Diverse mechanisms of action rard Lambeau c, Toni Petan a, * Vesna Brglez a, b, Ge Department of Molecular and Biomedical Sciences, Jozef Stefan Institute, Ljubljana, Slovenia Jozef Stefan International Postgraduate School, Ljubljana, Slovenia c Institut de Pharmacologie Mol eculaire et Cellulaire, CNRS et Universit e de Nice Sophia Antipolis, UMR 7275, Sophia Antipolis, Valbonne, France a


a r t i c l e i n f o

a b s t r a c t

Article history: Received 16 August 2014 Accepted 25 September 2014 Available online 5 October 2014

Secreted phospholipases A2 (sPLA2s) hydrolyse cell and lipoprotein phospholipid membranes to release free fatty acids and lysophospholipids, and can also bind to specific proteins. Several sPLA2s have been associated with various cancers, including prostate, colon, gastric, lung and breast cancers, yet, their role is controversial and seems to be dependent on the cancer type, the local microenvironment and the enzyme studied. There is strong evidence that the expression of some sPLA2s, most notably the group IIA, III and X enzymes, is dysregulated in various malignant tissues, where, as described in a number of in vitro and in vivo studies using mouse models and according to correlations between sPLA2 expression and patient survival, a particular enzyme may exert either a pro- or an anti-tumourigenic role. It is becoming clear that there are multiple, context-dependent mechanisms of action of sPLA2s in different cancers. First, the role of sPLA2s in cancer has traditionally been associated with their enzymatic activity and ability to participate in the release of potent biologically active lipid mediators, in particular arachidonic acid-derived eicosanoids, which promote tumourigenesis by stimulating cell proliferation and cell survival, by abrogating apoptosis and by increasing local inflammation and angiogenesis. Second, several biological effects of sPLA2s were found to be independent of sPLA2 enzymatic activity, arguing for a receptor-mediated mechanism of action. Finally, recent studies have implicated sPLA2s in the regulation of basal lipid metabolism, opening a new window to the understanding of the diverse roles of sPLA2s in cancer. In this short review, we highlight the newest findings on the biological roles of sPLA2s in cancer, with emphasis on their diverse mechanisms of action.  te  française de biochimie et biologie Mole culaire (SFBBM). All rights © 2014 Elsevier B.V. and Socie reserved.

Keywords: Cancer Secreted phospholipase A2 Lipid mediator Lipid metabolism Fatty acids Arachidonic acid

1. Secreted phospholipases A2 (sPLA2s)

Abbreviations: AA, arachidonic acid; ACC, acetyl-CoA carboxylase; AMPK, AMPactivated protein kinase; cPLA2a, cytosolic group IVA phospholipase A2; CPT1, carnitine palmitoyltransferase 1; EGFR, epidermal growth factor receptor; FA, fatty acid; ERK, extracellular signal-regulated kinase; FAS, fatty acid synthase; LD, lipid droplet; LPC, lysophosphatidylcholine; MAPK, mitogen-activated protein kinase; sPLA2, secreted phospholipase A2; PG, prostaglandin; PGE2, prostaglandin E2; PLA2R1, M-type receptor for secreted phospholipases A2; PUFA, polyunsaturated fatty acid; SCD-1, stearoyl-CoA desaturase-1; SREBP-1, sterol regulatory elementbinding protein; TAG, triacylglycerol. * Corresponding author. Department of Molecular and Biomedical Sciences, Jo zef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia. Tel.: þ386 1 477 3713; fax: þ386 1 477 3984. E-mail address: [email protected] (T. Petan). 1 sPLA2 enzymes are abbreviated with a lowercase letter indicating the species of origin (h, human; m, mouse) and with uppercase letters and Roman numerals denoting the sPLA2 group (GIB, GIIA, GIII, GX and GXIIB).

Secreted phospholipases A2 (sPLA2s)1 are lipolytic enzymes that act on membrane glycerophospholipids to release free fatty acids (FAs) and lysophospholipids by catalysing the hydrolysis of their sn-2 ester bond [1e3]. These low molecular mass, disulphiderich and Ca2þ-dependent enzymes are secreted from a variety of cells and act in autocrine or paracrine manner on cell membranes and other extracellular phospholipid substrates, such as lipoproteins and microvesicles, as well as bacterial and viral membranes [2]. There are eleven sPLA2 genes in humans and twelve in mice, encoding nine and ten active enzymes, respectively, and two sPLA2-like proteins. They display different tissue and cell expression patterns and differ significantly in their structure, which in turn affects their secretion, enzymatic activity and ability to bind to several known receptors [1e4]. They also display specific enzymatic preferences for binding to and hydrolysis of different types of phospholipids, with some enzymes showing a net preference for anionic or zwitterionic phospholipid substrates and  te  française de biochimie et biologie Mole culaire (SFBBM). All rights reserved. 0300-9084/© 2014 Elsevier B.V. and Socie

[12,18] [10,11,15e17] ND Shorter patient survival

[13,14,18,19] Shorter patient survival

Increased Increased GIIA GIIA Oesophageal Prostate

ND, not determined or not reported.

Increased Increased


Pro-tumourigenic Pro-tumourigenic


GIIA Gastric


Increased cell proliferation Increased cell proliferation

Knockdown of GIIA results in slower growth of xenograft tumours in mice ND Inhibition of GIIA results in slower growth of xenograft tumours in mice Increased cell proliferation; lower apoptosis

ND Reduction of cell migration and invasiveness

Increased in early-, decreased in late-stage tumours Increased Increased

Increased cell proliferation Increased

Pro- and/or antitumourigenic Anti-tumourigenic GX


Increased cell proliferation Increased Pro-tumourigenic GIII


Pro- and/or antitumourigenic GIIA Colon

Pro-tumourigenic GX



Genetic variant is associated with higher risk of cancer Longer patient survival; less frequent metastasis Longer patient survival; less frequent metastasis


[25e32,44,46] ND

Suppression of tumourigenesis; increased xenograft tumour size Increased xenograft tumour size ND

[57,58] ND ND

Increased cell proliferation; resistance to apoptosis Increased cell proliferation Increased in invasive and luminal tumours Increased

[53e55,57] Shorter patient survival ND ND Increased Pro-tumourigenic GIIA Breast

High in HER2-positive cells High in luminal-like, low in basal-like cells Increased

References Association with clinicopathological features and survival Effects in vivo Effects in vitro Expression in patients (serum and/or tumours) Expression in vitro Role

Aberrant expression of various human sPLA2s in tumours and cancer cells has been associated with the pathology of several types of malignancies, including, but not limited to, cancers of the colon, breast, stomach, oesophagus, ovaries and prostate (for a concise review see Ref. [9]), but the functional roles of sPLA2s are incompletely understood and seem to be dependent on the enzyme studied, the tissue and cancer type involved (Table 1). It must be noted that the majority of mechanistic and functional reports to date rely on in vitro cell culture and basic in vivo mouse model studies, and that a clear and unequivocal role in the development or progression of cancer has not been proven for any of the sPLA2 enzymes. Among sPLA2s, the group IIA (GIIA) and X (GX) enzymes are widely expressed in different tissues, are highly enzymatically active [1e3,5], and are also the most studied sPLA2s in cancer so far. It should thus not be surprising to the reader that the apparent focus of this mini-review is on these two enzymes, although every effort was made to include all relevant existing reports on the emerging role of other members of the sPLA2 family in cancer as well. The expression of the human group IIA (hGIIA) sPLA2 is high in prostate [10,11], oesophageal [12] and lung [13] cancer cells in vitro. In mouse xenograft models, inhibition of hGIIA sPLA2 in prostate [10] and lung [14] cancer cells, when implanted into nude mice, results in smaller tumours. In humans, the expression of hGIIA sPLA2 is increased in the serum or tumours of patients with prostate [10,11,15e17], oesophageal [18] and lung cancer [13,18,19], and importantly, it is associated with poorer patient survival in prostate [15] and lung cancer [19]. Of interest, recent in vitro results suggest that the lung cancer phenotype is supported by hGIIA sPLA2, which was found to be overexpressed in lung cancer stem cells relative to their non-stem cell counterparts [20]. The elevated levels of hGIIA in the plasma of lung and prostate cancer patients [11,19] have led to suggestions of a potential biomarker role for the enzyme. However, at least in the case of prostate cancer, the presence of high concentrations of hGIIA in serum may not reflect neoplastic transformation, but rather inflammation, characteristic also of benign prostate hyperplasia [16,17]. Based on the above findings, a pro-tumourigenic role of the enzyme has been suggested in prostate, oesophageal and lung cancer. No data is available on the role of other sPLA2s in these cancers. On the contrary, the increased expression of hGIIA sPLA2 in gastric cancer cell lines and in tumours of patients with gastric cancer appears to be associated with an anti-tumourigenic role of the enzyme, as it reduces cell migration and invasiveness in vitro, its expression correlates with longer survival and is a predictor of a

sPLA2 enzyme

2. Expression and functional role of sPLA2s in cancer



some being almost devoid of enzymatic activity [1,5], suggesting distinct and non-redundant biological roles for each sPLA2 [5]. The cellular effects of sPLA2s have most commonly been associated with the release of arachidonic acid (AA) and its eicosanoid metabolites, as well as signalling triggered by binding to specific receptors [1e3,6e8]. However, sPLA2 activity also leads to the release of a mixture of other bioactive lipids, such as mono- and polyunsaturated FAs (PUFAs), including omega-3 PUFAs, and lysophospholipids, such as lysophosphatidylcholine (LPC). Many, if not all, of these lipids have various signalling roles, act as biosynthetic precursors or have direct metabolic roles. Collectively, the multitude of phospholipid substrates, the primary and secondary lipid products of sPLA2 activity and the various known cellular effects of sPLA2s provide a rationale for their involvement in a variety of physiological processes and diseases, including lipid digestion and remodelling, acute and chronic inflammatory diseases, cardiovascular diseases, reproduction, host defence against infections and cancer [2,3].

Table 1 Functional role of sPLA2s in cancer. Studies in which the mechanisms of action or functional roles of sPLA2s were not assessed were mostly omitted from this table. Please refer to Ref. [9] for a thorough summary of such studies published before 2010 and to the text for studies published after 2010.

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favourable outcome for patients with gastric cancer [21e24]. Interestingly, the expression of hGIIA sPLA2 mRNA was found to be elevated in primary, early-stage gastric tumours, but decreased in late-stage metastatic tumours, suggesting that the loss of hGIIA sPLA2 activity may contribute to the development of more aggressive tumours [21]. The expression of the hGIIA sPLA2 is also upregulated in colon cancer, but its role remains controversial [2,25e28], partly due to the difficulty of extrapolating results from mouse to human malignancies and partly due to inconsistent results both in mouse models and in human tissues. For instance, it has been suggested that the mouse GIIA (mGIIA) sPLA2 has a protective role in colon cancer, based on its ability to suppress tumourigenesis in several mouse models [26,29e31], possibly by promoting mucosal health through its bactericidal properties, by modulating the inflammatory response and Wnt signalling or by activating pro-apoptotic mechanisms [32]. However, the expression of mGIIA is higher in the small intestine than in the colon, possibly suggesting a more specific role of the enzyme in the former. In agreement with the mouse data, the hGIIA enzyme and several other sPLA2s have indeed been shown to induce cell death and senescence, or accelerate ongoing cell death processes, in several normal and tumour cell lines in vitro [33e40]. However, the expression of mGIIA sPLA2 in a subcutaneous xenograft mouse model resulted in increased tumour size, arguing for a tumour promoting role of the enzyme [25]. Additionally, it has been suggested that the enzyme may suppress small intestine and colon carcinogenesis at early stages of tumour development, while promoting it at later stages [25,26]. In humans, mutations in the PLA2G2A gene have been ruled out as the basis for the suggested tumour suppressor role of the enzyme in colon tumourigenesis [41e43], but, as inferred from mouse model studies, it is likely that the aberrant expression and activity of hGIIA sPLA2 in colon tumours [28,44] affects malignant transformation through alterations in lipid mediator production, cell signalling and effects on the microbiome [2,32,45]. Collectively, these results suggest that the GIIA sPLA2 may have either a pro- or an antitumourigenic role in colon cancer, possibly depending on tumour subtype, stage, specific microenvironment or part of the tumour [46]. Two other sPLA2s, the group III (GIII) and the GX sPLA2s, have been implicated in colon carcinogenesis. Recent data have shown a significant up-regulation of the human GIII (hGIII) sPLA2 in colon cancer tissues [27,47]. A pro-tumourigenic role has been suggested for the enzyme, since its stable overexpression stimulates colon cancer cell proliferation and results in larger tumours upon implantation of the cells into nude mice [47]. Furthermore, a genetic variant of the PLA2G3 gene has been associated with a higher risk of colon cancer [48]. The GX sPLA2 is expressed at very high levels in the colon [27,49,50], it is reported to be elevated in tumour biopsies of patients with colon cancer, specifically in metastatic tissues [51], and in peritumoural colon carcinoma tissue in comparison with the central region [46]. Its functional role in colon cancer is, however, less clear, since exogenous addition of the enzyme stimulates mouse colon cancer cell proliferation in vitro, thus suggesting a protumourigenic role for the enzyme [50], while the inverse association of its expression with metastasis and longer patient survival [51] argues for an anti-tumourigenic role of the human GX (hGX) sPLA2 in colon cancer. Interestingly, the expression of group XIIB (GXIIB) sPLA2 is also elevated in colon cancer and decreased in cancer of the small intestine, but the significance of these findings has not been investigated further [52]. There have only been a few studies investigating sPLA2 expression in breast cancer, and these consistently suggest a protumourigenic role for the hGIIA sPLA2 enzyme. Its expression was found to be elevated in advanced breast cancer [53,54] and low levels

of hGIIA sPLA2 correlate with longer patient survival [55]. Our recent in silico analysis of primary tumours using the Oncomine depository of microarray data [56] revealed contradictory results on hGIIA sPLA2 gene expression, with reports of either up- or downregulation, while the genes encoding hGIII and hGX sPLA2s were found to be clearly upregulated in the majority of breast cancer biopsies [57]. Interestingly, the expression of hGX sPLA2 was lower in highly invasive triple negative and basal-like breast cancer cells relative to the less aggressive tumours of luminal origin, both in biopsies and cultured cells [57]. The differential expression suggests distinct, cell typedependent roles for these sPLA2s in breast tumours with different phenotypes and molecular signatures. Indeed, exogenous hGX sPLA2 displays either a stimulative or no effect on the growth and survival of breast cancer cells with different tumourigenic properties [58]. This is in line with the idea that the expression and role of a particular sPLA2 in a certain type of cancer is strongly influenced by the genetic background and phenotype of different tumour subtypes reflecting the heterogeneity of the disease. This may explain some of the contradictory reports and the difficulties to define a role of a particular sPLA2 in a particular cancer using cell lines and mouse models. Clearly, more data is needed to validate the role of each sPLA2 in different types of cancer. Elevated hGIIA sPLA2 protein concentrations have also been found in the serum of patients with other malignancies, such as head and neck, pancreatic and hepatocellular carcinomas, as well as myeloma and non-Hodgkin's lymphoma [18]. Although the increased plasma levels of hGIIA sPLA2 may be the result of cancerassociated or cancer-independent inflammatory processes [16,17], and not malignancy itself, its expression may nevertheless have a prognostic value in patients with different tumours [18]. Indeed, several sPLA2s have been suggested as promising prognostic indicators due to their association with shorter or longer patient survival, for example hGIIA in prostate [15], lung [19], gastric [22e24] and breast cancer [55], and hGX sPLA2 in colon cancer [51]. In addition, several studies have pointed to the potential use of sPLA2 expression in tumour tissues as a biomarker for patients with cancer, such as hGIII [27] and hGX sPLA2s [51] in tumours of the colon. The mechanisms responsible for the altered expression of sPLA2s in various cancers remain to be elucidated. Only a few reports have as yet investigated the events leading to the modulation of sPLA2 expression in tumours. In some cases, silencing of sPLA2 expression by epigenetic mechanisms has been proposed to play a role in tumourigenesis. For example, hGIIA has been shown to be epigenetically silenced by means of DNA methylation and/or histone acetylation in late-stage metastatic gastric tumours [21], prostate cancer and leukaemia cells [59,60], as well as in invasive breast cancer cells, in which hGIII and hGX are also silenced, most prominently in triple negative cells [57]. In addition to epigenetic mechanisms, pro-inflammatory factors, such as cytokines, can increase the expression of hGIIA in a cell-type dependent manner, for instance in hepatoma [61] and prostate cancer cells [17]. Little is known about the signalling events and transcriptional machinery, leading to increased expression of sPLA2s in cancer, yet the published studies point to several growth factor signalling pathways. For example, a series of studies has shown that hGIIA sPLA2 is overexpressed and secreted by androgen-independent prostate cancer cells due to elevated signalling of the HER/HER2PI3K-Akt-NF-kB pathway [11,15,62], while the b-catenin-dependent Wnt signalling was identified as a major upstream regulator of hGIIA sPLA2 expression in gastric cancer cells [21,63]. Collectively, the limited amount of data available so far suggest that the modulated expression of sPLA2s in cancer may be a consequence of dysregulated epigenetic, growth factor signalling and/or inflammatory mechanisms, which are often cancer- and cell typespecific.

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3. Mechanisms of action of sPLA2s in cancer 3.1. sPLA2s and activation of lipid signalling pathways in cancer cells It is commonly believed that sPLA2s can participate in the development of cancer by multiple, enzymatic activity-dependent mechanisms (Fig. 1). Historically, the role of sPLA2s in various diseases, including cancer, has been associated with AA metabolism and stimulation of eicosanoid synthesis [9,49,50]. AA is a substrate for intracellular biochemical pathways that generate over hundred potent autocrine and paracrine lipid mediators, eicosanoids, involved in cell proliferation, survival, differentiation, angiogenesis, inflammation and immunity [64]. Impaired regulation of any of these cellular functions may contribute to the critical steps in cancer growth and metastasis. Indeed, the levels of prostaglandins (PG) and leukotrienes, as well as their biosynthetic enzymes, are dysregulated in various cancers [65,66]. Increased expression of cyclooxygenase-2 (COX-2), an inducible enzyme catalysing the first step of AA conversion into PGs, has been associated with a number of malignancies [67e69]. Additionally, gene knockouts of important enzymes involved in prostanoid metabolism (the cytosolic group IVA PLA2 (cPLA2a), COX-1, COX-2, PGE synthase and prostanoid receptors) lead to reduced tumour development in mice [65].


Therefore, it is not surprising that sPLA2s, as possible regulators of the supply of free AA to its metabolic and signalling pathways, have emerged in the last decade as promising targets in cancer prevention and therapy [70]. Several sPLA2s, especially the GX sPLA2, readily release AA from cell membranes of cancer cells [49,50,71,72], and stimulate, either directly or in coordination with cPLA2a, COX-2-dependent eicosanoid synthesis, including the production of the mitogenic prostaglandin E2 (PGE2) [66,73]. Overexpression of hGIII sPLA2 in colon cancer cells also results in increased enzyme activity-dependent AA release, PGE2 production and higher proliferation rates [47]. The hGIII sPLA2 stimulates PGE2 production also in prostate cancer cells [47]. However, despite many studies focused on sPLA2-induced AA release and eicosanoid metabolism, neither the exact molecular mechanisms involved in the effects of sPLA2 on cell fate nor the relevance of these activities in vivo in both mouse cancer models and in human cancers have been elucidated [1]. For example, hGX sPLA2 induces colon cancer cell proliferation in vitro by releasing a complex mixture of mitogenic FAs, lysophospholipids and eicosanoids, but, surprisingly, the proliferative effects of hGX sPLA2 are not dependent on the mitogenic activity of AA-derived PG or LPCderived lysophosphatidic acid signalling [50]. Similarly, experiments with pharmacological inhibitors suggest that the cPLA2aand COX-mediated AA metabolism is not necessary for the pro-

Fig. 1. Different mechanisms of action of sPLA2s in cancer. A particular sPLA2 isoform may affect cancer cell growth parameters through one, two or several of the described mechanisms in a sequential or parallel manner, depending on the enzyme characteristics, the released products and their metabolites, the cancer cell (pheno)type and the tumour microenvironment. Some of these mechanisms may affect tumour growth in a pro- (green) and others in an anti-tumourigenic (red) manner, the final outcome in a particular setting in vivo being likely dependent on the net balance between the two. sPLA2s can function as: 1) enzymes, hydrolysing phospholipids and thus releasing a complex mixture of various FAs and lysophospholipids; or 2) ligands for their receptors and binding proteins, such as the M-type PLA2 receptor and integrins. sPLA2s can exert their enzymatic activitydependent roles either by: a) modulation of basic lipid metabolism by stimulating lipid droplet formation and mitochondrial oxidative metabolism, most notably affecting the expression of key FA oxidation enzymes, activating AMPK and Akt kinases, while at the same time suppressing the expression of SREBP-1 and other genes involved in FA synthesis. sPLA2s can in this way modulate the energy and redox balance in the cell, which leads to increased survival and proliferation capabilities of the cells, in particular resistance to metabolic stress-induced apoptosis; b) bioactive lipid signalling through direct action of the released FAs and lysophospholipids or their conversion to other biologically active lipid mediators, in particular, the production of (often pro-inflammatory) eicosanoid metabolites of AA. These effects are commonly associated with the activation of cPLA2a and of the EGFR, MAPK, PI3K/Akt and NF-kB pathways, leading to increased proliferation of cancer cells. On the other hand, receptor-mediated signalling usually results in the activation of the MAPK, PKC and PI3K/Akt/mTOR cascades and thus proliferation and resistance to apoptosis in cancer cells. In some cases, the roles of enzymatic activity or receptor-mediated mechanisms have not been investigated or clarified, e.g. the inhibition of invasion and metastasis by hGIIA sPLA2 in gastric cancer cells [21]. Likewise, the mechanisms involved in some of the reported tumour suppressive effects of sPLA2s are not clear, and may be related to their ability to induce apoptosis and senescence in some types of cells. Abbreviations: AA, arachidonic acid; AMPK, AMP-activated protein kinase; cPLA2a, cytosolic group IVA phospholipase A2; DHA, docosahexaenoic acid; EGFR, epidermal growth factor receptor; EPA, eicosapentaenoic acid; FA, fatty acid; LA, linoleic acid; LPC/E/S, lysophosphatidylcholine/ethanolamine/serine; LPA, lysophosphatidic acid; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; OA, oleic acid; PKC, protein kinase C; SREBP-1, sterol regulatory element-binding protein 1.


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survival effects of hGX sPLA2 in breast cancer cells [58]. In both cases, the in vivo relevance of these findings is unknown. In prostate cancer, increased eicosanoid production has been observed in tumours in comparison with benign tissues [74,75], which can be attributed either to the action of sPLA2s, cPLA2a or calcium-independent PLA2s [9,76,77]. Interestingly, the enzymatic activity-dependent proliferative effect of hGIIA sPLA2 in prostate cancer cells was dependent on the activation of cPLA2a [10,11]. On the other hand, the pro-tumourigenic effects of hGIIA sPLA2 in lung cancer [13,14] and oesophageal cancer cells [78] have been associated with its ability to activate NF-kB signalling [13,14,78,79]. In lung cancer cells, hGIIA sPLA2 signals through the epidermal growth factor receptor (EGFR), possibly acting as a ligand [79], and it also modulates mitogen-activated protein kinase (MAPK) signalling [13]. In gastric cancer, the hGIIA sPLA2 enzyme inhibited cell invasion and metastasis, at least in part, by inhibiting the S100A4 metastasis mediator gene, however, its detailed anti-tumourigenic mechanism remains unexplained [21]. Of interest is the idea that hGIIA sPLA2 may also indirectly affect gastric cancer progression by altering gastrointestinal flora and the tumour microenvironment through its anti-bacterial activity [2,28,44,45]. The hydrolytic activity of sPLA2s on cell membranes also results in the release of lysophospholipids, whose roles in tumour growth and metastasis are emerging [70,80e84]. Although the sPLA2 enzymatic activity-dependent cellular effects reported have rarely been associated with lysophospholipids [50,85], this might be a consequence of the predominant focus of most laboratories on sPLA2-induced changes in AA metabolism and pro-inflammatory signalling. On the other hand, some of the products of sPLA2mediated phospholipid hydrolysis can have an anti-inflammatory effect [77]. For example, sPLA2s release PUFAs from cell membrane phospholipids, including omega-3 PUFAs, which are precursors for the synthesis of the anti-inflammatory and proresolving mediators resolvins, protectins and maresins [86,87]. Indeed, it has been shown recently that the group IID sPLA2 expressed in dendritic cells and macrophages is involved in the generation of resolvin D1 during contact hypersensitive reactions in vivo resulting in amelioration of inflammation [88]. The various products of sPLA2 activity and their pleiotropic effects clearly complicate the elucidation of the roles of sPLA2s in cancer, as the effects can often be contradictory, depending on the response of each individual cell type to the various FAs, lysophospholipids, and their metabolic products. 3.2. sPLA2s and alterations of lipid metabolism in cancer cells Studies in the last decade have revealed that in addition to the Warburg effect and the reprogramming of glutamine metabolism in cancer, dysregulated lipid metabolism is one of the fundamental metabolic alterations that enable cancer cell survival and sustain rapid growth and proliferation [89e92]. It has become clear that changes in FA synthesis, lipolysis, membrane phospholipid hydrolysis and reacylation pathways are required for cancer cell growth [83,92e94]. An increased availability of FAs is needed for the synthesis of membranes and signalling molecules that are indispensable for rapid cell growth and division in cancer, and limiting FA supply may prevent cell proliferation in tumours [95]. Targeting the mechanisms underlying these transformations of phospholipid and lipid metabolism is a promising strategy for the development of selective antineoplastic agents. sPLA2s may affect FA and lipid metabolism in different ways. sPLA2s are known to be rather unspecific regarding the nature of the FA acyl chain present at the sn-2 position of phospholipids. Hence, besides AA (20:4n6), catalytically active sPLA2s also

release numerous other mono- and polyunsaturated FAs, including the most abundant oleic (18:1n9) and linoleic (18:2n6) acids, as well as the omega-3 PUFAs, docosahexaenoic (DHA; 22:6n3) and eicosapentaenoic (EPA; 20:5n3) acids, which could all influence lipid metabolism and tumourigenesis in a variety of ways [77,95e99]. FAs can act as signalling molecules and can modulate major growth and metabolic pathways in the cell by acting as ligands for peroxisome proliferator-activated receptors (PPARs) [100e102], by modulating liver X receptor (LXR) and sterol regulatory element-binding protein 1 (SREBP-1) transcription factor activities [100,103], and even by binding to G protein coupledreceptors and activating growth and survival signalling cascades, such as the PI3K pathway [96,104]. However, FAs display a plethora of indirect signalling and metabolic effects as well, since they can be remodelled into membrane phospholipids, catabolised through mitochondrial FA oxidation or esterified into triacylglycerols (TAGs), which are stored in lipid droplets (LDs) in the cytosol of most cells, including cancer cells [105e107]. Several enzymes critical for the regulation of FA availability in the cell through synthesis, such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC) and stearoyl-CoA desaturase-1 (SCD-1) [95,108], and through lipolysis, such as monoacylglycerol lipase (MAGL) [94,109], have been clearly associated with cancer. In addition, evidence is mounting for an important role of mitochondrial FA oxidation in tumourigenesis as well [99,110,111]. Interestingly, several recent reports have revealed that sPLA2s may affect lipid metabolism in various physiological and pathophysiological settings, including steroid hormone synthesis in adrenal glands [112], adipogenesis [113], lipid digestion in the gut and diet-induced obesity [114,115], stimulation of lipid accumulation and foam cell formation from macrophages [2], but the possible associations between sPLA2s, lipid metabolism and cancer have not been explored until recently. We have shown that hGX sPLA2 enables the survival of highly metastatic, Ras-driven invasive breast cancer cells through a novel mechanism involving global changes in lipid energy metabolism [58] (Fig. 2). FAs released by sPLA2 membrane hydrolysis are incorporated into TAGs and stored in cytosolic LDs, which provide a long-term resistance to nutrient and growth factor starvationinduced cell death. hGX sPLA2 activity induces significant changes in cellular FA synthesis, oxidation and storage, including an increase in the expression of rate-limiting FA oxidation enzymes, carnitine palmitoyltransferase 1 (CPT1) and very long-chain acylCoA dehydrogenase (VLCAD), and the LD-coating protein perilipin 2, as well as a decrease in the expression of genes encoding the major FA synthesis proteins (SREBP-1, ACC, FAS and SCD-1). The sPLA2-induced LD formation in breast cancer cells is accompanied by the activation of AMP-activated protein kinase (AMPK), a central metabolic sensor and reciprocal regulator of cellular metabolism, shown recently to enable cancer cell survival during energy stress in vivo by suppressing FA synthesis and activating FA oxidation [111,116]. Accordingly, the stimulating effects of hGX sPLA2 on LD formation and cell survival were abolished by etomoxir, an irreversible inhibitor of mitochondrial FA oxidation, while bezafibrate, a pan-PPAR agonist and activator of FA oxidation, supported hGXinduced LD formation and survival. Cancer cell membrane hydrolysis by hGX sPLA2 thus induces global changes in cell metabolism, which provide a minimal immediate proliferative advantage during growth under optimal conditions, but confer to the breast cancer cells a sustained ability to resist apoptosis during nutrient and growth factor limitation. In light of these new results, the previously reported and typically modest mitogenic effects of sPLA2s in colon cancer and other cells [10,12,25,47,50] could, at least in some of these studies, be in fact a consequence of underlying changes in basic lipid metabolism and a pro-survival action, which is evident only under stressful conditions for the cell [58]. Although awaiting

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Fig. 2. The proposed mechanism of human group X (hGX) sPLA2-mediated modulation of basal lipid metabolism, survival and proliferation of breast cancer cells. The free FAs released by the phospholipolytic activity of hGX sPLA2 on breast cancer cell membranes are targeted to: 1) triacylglycerol (TAG) synthesis and storage in lipid droplets (LDs), which are extensively metabolised during nutrient and growth factor deprivation through lipolysis and FA oxidation; 2) mitochondrial FA oxidation, which provides a minimal growth advantage to the cells during optimal growth conditions, but confers a sustained ability to resist cell death during metabolic stress by maintaining the energy and redox balance in the cell, most probably by providing ATP and NADPH. hGX sPLA2 increases the expression of the major FA oxidation enzymes CPT1A and VLCAD, as well as the LD-coating protein PLIN2, while downregulating the expression of the SREBP-1 transcription factor and the ACC, FAS and SCD-1 enzymes responsible for de novo FA synthesis. hGX sPLA2-induced LD formation leads to the activation of AMPK, a central regulator of cellular metabolism, which may be responsible for many of the observed metabolic and pro-survival signalling changes. AMPK responds to energy stress by suppressing ATP-consuming processes, including FA, cholesterol and TAG synthesis, while stimulating ATP-producing processes, such as mitochondrial biogenesis, FA oxidation and lipolysis. One of the major effects of AMPK in most cell types is phosphorylation and inactivation of ACC, leading to suppression of FA synthesis, and also to a reciprocal stimulation of CPT1A activity and FA oxidation due to reduction in malonyl-CoA levels. Interestingly, both the LD-inducing and pro-survival effects of hGX sPLA2 are abolished by etomoxir, an irreversible inhibitor of CPT1A [58]. Metabolic pathways and reactions are represented by green arrows, while black arrows and red blunt arrows represent signalling. Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; CPT1A, carnitine palmitoyltransferase 1A; FA, fatty acid; FAS, fatty acid synthase; LD, lipid droplet; MAPK, mitogen-activated protein kinase; PLIN2, perilipin 2; SCD-1, stearoyl-CoA desaturase-1; SREBP-1, sterol regulatory element-binding protein; TAG, triacylglycerol; VLCAD, very long-chain acyl-CoA dehydrogenase.

confirmation in vivo, these results establish hGX sPLA2 as a novel modulator of lipid metabolism that promotes the growth and survival of invasive breast cancer cells by stimulating LD accumulation and altering FA metabolism. Interestingly, it was found recently that Ras oncogene-driven cancer cells can bypass de novo lipogenesis requirements by scavenging FAs mainly from serum lysophospholipids [83,117]. It is therefore conceivable that Ras-driven cancer cells can take-up lysophospholipids released by sPLA2 membrane hydrolysis more effectively than cells without Ras activation, which could explain the differential potency of hGX sPLA2 to induce LD formation and prevent apoptosis in different breast cancer cells [58] and perhaps also the difficulties in assigning a clear role of sPLA2s in some other cancers. The Ras-driven mechanism of lysophospholipid scavenging is likely only one of the many cancer cell phenotypes that may dictate the role of a particular sPLA2 in different types of cancer. 3.3. Enzymatic activity-independent roles of sPLA2s in cancer cells PLA2R1, a mannose receptor family member, is the most studied sPLA2 receptor [118]. However, the physiological relevance of sPLA2-PLA2R1 binding is still poorly understood, mainly due to the apparent limited binding of human sPLA2s to human PLA2R1 [119], which contrasts observations in the mouse species [120]. Nevertheless, sPLA2-PLA2R1 binding inhibits sPLA2 catalytic activity and promotes its internalisation and degradation [1,121,122], suggesting

that PLA2R1 could counteract the effect of sPLA2s in various cancers or even enhance it by targeting sPLA2s to a specific cell compartment. Interestingly, it has been shown recently that PLA2R1 exerts a variety of functions in cancer cells (for a concise review, see Ref. [122]). Its expression is lower in numerous cancers [123] and promoter hypermethylation has been observed for this gene in leukaemia and clear cell renal cell carcinoma-derived cells [124,125], suggesting a tumour suppressive role. In line with this, gain and loss of function experiments in vitro and in vivo have shown that PLA2R1 promotes senescence, apoptosis and inhibition of transformation, thereby acting as a tumour suppressor [38,122,123,125,126]. Surprisingly, all of these functions seem to be independent of sPLA2 binding [122]. On the other hand, binding of sPLA2 to PLA2R1 has been proposed to activate many signalling pathways and target sPLA2 to specific intracellular compartments [121,122,127e129]. Although several studies have suggested that sPLA2-PLA2R1 binding may be important in cancer, only one study pointed to a possible association between PLA2R1 knockdown and sPLA2 expression in prostate cancer [130], while direct evidence is still lacking. In vitro studies have shown that certain biological effects of sPLA2s are independent of their enzymatic activity, pointing to a receptor-mediated mechanism of action, yet the causal sPLA2 binding site has not been identified and appears to be different from PLA2R1. For instance, human group IB (hGIB) sPLA2 can


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stimulate the proliferation of pancreatic cells through the activation of the MAPK cascade [127,131]. Since a single class of binding sites for hGIB sPLA2 was identified in these cells, since lysophospholipids did not induce cell proliferation [131] and since the enzymatic activity of hGIB sPLA2 was suppressed upon binding to the receptor [127], it seems likely that the proliferative effect of hGIB sPLA2 is independent of its enzymatic activity and likely a consequence of the sPLA2 interacting with an unidentified binding site. Similar results were obtained in an astrocytoma cell line, where treatment with porcine GIB or hGIIA sPLA2 leads to the activation of cPLA2a and the MAPK kinase, PI3K/Akt/mTOR and protein kinase C (PKC) pathways [132e135]. Interestingly, the same effects were achieved in the absence of extracellular Ca2þ, suggesting that the enzymatic activity of hGIIA sPLA2 is not important for the activation of these signalling pathways [136], or for the increased proliferation and the resistance to apoptosis of these cells [132,133]. The mechanism of action of hGIIA sPLA2 in astrocytoma cells seems to be associated with inflammation, especially with pro-inflammatory cytokine signalling [133], accumulation of reactive oxygen species [134] and activation of EGFR [135]. These findings are reminiscent of a study in rat mesangial cells showing that hGIIA sPLA2 released after cell stimulation with tumour necrosis factor-a further induces its own expression by a receptor-mediated mechanism of action followed by activation of cPLA2a and PPARa, but independently of hGIIA enzymatic activity and PLA2R1 binding [137]. The reports on other sPLA2 binding proteins and their role in cancer are limited. Only one study has shown a link between an sPLA2 binding to integrins and increased proliferation of monocytes [138]. In this setting, treatment with either wild-type hGIIA sPLA2 or its enzymatically inactive mutant, but not the integrin bindingdefective mutant, resulted in augmented ERK-dependent proliferation of monocytic lymphoma and leukaemia cells [138], leading the authors to conclude that the pro-inflammatory and proliferative action of hGIIA sPLA2 relies on its binding to integrins and not its enzymatic activity. 4. Conclusions The expression of several sPLA2s is altered in various cancer cells, but they can also be expressed from the neighbouring stromal and immune cells at primary or metastatic tumour sites [2,113]. Once secreted, sPLA2s may act in an autocrine or paracrine manner as ligands for different receptors or as enzymes on cellular phospholipids or on other extracellular phospholipid substrates to alter the availability of FAs and lysophospholipids in the microenvironment and induce metabolic and signalling changes in the tumour [58,83,116]. Their direct action on cancer cells may include changes in cell growth, survival, migration and invasion, or, alternatively, they might indirectly influence tumour growth by altering the microenvironment or by inducing inflammation. Regardless of their cellular origin, it is clear that sPLA2s may exert either a pro- or an anti-tumourigenic role, depending on the tissue, cancer type and the enzyme studied. This nowadays comes as no surprise given the differential tissue expression patterns of sPLA2s, the diversity of extracellular target membranes and the plethora of bioactive lipid products that are released from cell membranes as the result of sPLA2 enzymatic activity [2,50]. The above controversies may explain the contradictory reports and difficulty in assigning a unique and similar role for a particular sPLA2 in one cancer type versus another. In fact, in one cancer type, the action of a particular sPLA2 may be multiple and sequential. For instance, once secreted in a tumour microenvironment, one sPLA2 may sequentially exert pro- and anti-tumourigenic roles depending on the other effectors present in the milieu and by one of the above mechanisms of action,

and only the overall net balance (i.e. the sum of pro- versus antitumourigenic effects) may be evident in in vivo situations when the effect of the sPLA2 is observed after several days or weeks. More studies are clearly needed in various mouse models of cancer, first, to clarify whether sPLA2s indeed play key in vivo roles in cancer, and second, to successfully apply the findings from in vitro and in vivo studies to human health. Regardless of the aforementioned limitations, such as differences in sPLA2 expression and function and in PLA2R1 binding preferences between mouse and human species, sPLA2s may, in the future, constitute a new class of cancer therapeutic targets. Their potential as cancer biomarkers has already been established, and owing to their small size and secretion to the milieu they can easily be targeted with inhibitors specific for a particular enzyme [139,140]. Collectively, most of the reported effects of sPLA2s in different cancer cells seem to be dependent on their enzymatic activity and release of AA and other lipid mediators, while a small number of emerging studies point to enzymatic activity-independent mechanisms. Recent results showing that sPLA2s can modulate basal lipid metabolism, and not only lipid signalling, shed a new light on both past and future studies. The different modes of action of sPLA2s in cancer also add another layer of complexity to their role in human (patho)physiology in general. Clearly, more work is still needed, especially in mice models, to further elucidate the major roles and underlying mechanism(s) of action of sPLA2s in cancer, be it dependent on lipid mediator production and signalling, basic lipid metabolism or binding to specific receptors and/or other proteins. Acknowledgements This work was supported by grant P1-0207 from the Slovenian Research Agency, by the French-Slovene partnership project BI-FR/ 12-13-PROTEUS-006, by fellowships 11012-7/2013-4 and 11012-23/ 2014-8 from the Slovene Human Resources Development and Scholarship Fund, and by CNRS, the Association for International Cancer Research and the Fondation ARC pour la recherche sur le cancer to G.L. References [1] G. Lambeau, M.H. Gelb, Biochemistry and physiology of mammalian secreted phospholipases A2, Annu. Rev. Biochem. 77 (2008) 495e520. [2] M. Murakami, Y. Taketomi, H. Sato, K. Yamamoto, Secreted phospholipase A2 revisited, J. Biochem. 150 (2011) 233e255. [3] M. Murakami, G. Lambeau, Emerging roles of secreted phospholipase A2 enzymes: an update, Biochimie 95 (2013) 43e50. [4] M. Murakami, Y. Taketomi, Y. Miki, H. Sato, K. Yamamoto, G. Lambeau, Emerging roles of secreted phospholipases A2 enzymes: the 3rd edition, Biochimie 107 (2014) 105e113. [5] A.G. Singer, F. Ghomashchi, C. Le Calvez, J. Bollinger, S. Bezzine, M. Rouault, et al., Interfacial kinetic and binding properties of the complete set of human and mouse groups I, II, V, X, and XII secreted phospholipases A2, J. Biol. Chem. 277 (2002) 48535e48549. [6] G. Lambeau, M. Lazdunski, Receptors for a growing family of secreted phospholipases A2, Trends Pharmacol. Sci. 20 (1999) 162e170. [7] K. Hanasaki, Mammalian phospholipase A2: phospholipase A2 receptor, Biol. Pharm. Bull. 27 (2004) 1165e1167. [8] M. Triggiani, F. Granata, G. Giannattasio, G. Marone, Secretory phospholipases A2 in inflammatory and allergic diseases: not just enzymes, J. Allergy Clin. Immunol. 116 (2005) 1000e1006. [9] K.F. Scott, M. Sajinovic, J. Hein, S. Nixdorf, P. Galettis, W. Liauw, et al., Emerging roles for phospholipase A2 enzymes in cancer, Biochimie 92 (2010) 601e610. [10] P. Sved, K.F. Scott, D. McLeod, N.J. King, J. Singh, T. Tsatralis, et al., Oncogenic action of secreted phospholipase A2 in prostate cancer, Cancer Res. 64 (2004) 6934e6940. [11] Z. Dong, Y. Liu, K.F. Scott, L. Levin, K. Gaitonde, R.B. Bracken, et al., Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer, Carcinogenesis 31 (2010) 1948e1955.

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Secreted phospholipases A2 in cancer: diverse mechanisms of action.

Secreted phospholipases A2 (sPLA2s) hydrolyse cell and lipoprotein phospholipid membranes to release free fatty acids and lysophospholipids, and can a...
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