Trans. Tianjin Univ. DOI 10.1007/s12209-016-0025-y

REVIEW

Role of Calcium-Independent Phospholipase A2 VIA in Mediating Neurological Disorder and Cancer Chang Y. Chung1 • Yu Shi1 • Austin R. Surendranath1 • Nasir Jalal1 Janak L. Pathak1 • Selvaraj Subramaniyam1

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Received: 19 April 2016 / Revised: 13 June 2016 / Accepted: 19 August 2016 Ó Tianjin University and Springer-Verlag Berlin Heidelberg 2016

Abstract Calcium-independent phospholipase A2 (iPLA2) belongs to the group VI family of phospholipase superfamily (PLA2) that catalyses the hydrolysis of glycerophospholipids at the sn-2 ester bond, producing unesterified fatty acids and 2-lysophospholipids. Research interests on iPLA2 have not been as significant as those on secretary PLA2 and cytosolic PLA2. However, more efforts have been made recently on understanding the expression, regulation and biological function of iPLA2. iPLA2 plays important roles in several biological processes, including signal transduction, phospholipid remodelling, eicosanoid formation, cell proliferation, cell differentiation and apoptosis. Modulation of iPLA2 activity can have prominent effects on cellular metabolism, central nervous system and cardiovascular functions. Thus, dysregulation iPLA2 can play a vital role in the pathogenesis of several diseases. The aim of this review is to provide the current understanding of the structure, function and regulation of group VI iPLA2 and highlight its potential mechanisms of action in mediating several neurological disorders and cancer. Keywords Calcium-independent phospholipase A2
Neurological disorders
Memory acquisition
Alzheimer’s disease
Infantile neuroaxonal dystrophy
Cancer

& Yu Shi [email protected] 1

School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China

Introduction Phospholipase A2 catalyses the hydrolysis of glycerophospholipids at the sn-2 ester bond and produces unesterified fatty acids such as arachidonic acid and 2-lysophospholipids [1]. Calcium-independent phospholipase A2 (iPLA2) belongs to the group VI family of phospholipase superfamily (PLA2) that catalyses the hydrolysis of glycerophospholipids without the requirement of calcium. Activation of iPLA2 leads to generation of biologically active lipid mediators such as arachidonic acid and lysophospholipids that can affect numerous cellular events. iPLA2 participates in several biological processes, including signal transduction, phospholipid remodelling, eicosanoid formation, cell proliferation, cell differentiation, apoptosis, maintenance of mitochondrial integrity, activation of store-operated channels, capacitative calcium influx, insulin secretion, bone formation and sperm development [2–4]. In recent years, there has been a growing interest in understanding the structure and functions of iPLA2 and its role in regulating cellular functions under physiological and also several pathological conditions, particularly neurological disorders and cancer [5–13]. Higher basal expression and activity of iPLA2 in the brain, compared to cytosolic PLA2 (cPLA2) and secretary PLA2 (sPLA2), are consistent with its suggested role in neurological disorders [14–16]. Due to insensitivity towards calcium, iPLA2 has been less scrutinised than cPLA2. However, the activation of iPLA2 has recently been shown to be regulated through various mechanisms, including subcellular localization, protein–protein interaction mediated by ankyrin repeats, binding of ATP, binding of calmodulin, phosphorylation and cleavage of iPLA2 by caspase and activation by

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hydrogen peroxide. However, the physiological role of iPLA2 in regulating neuronal cell function is still unclear. A growing body of literature has examined the involvement of iPLA2 in cellular signalling pathways that can link oxidative events to inflammatory responses in several neurodegenerative disorders. The aim of this review is to provide a better understanding of the structure, function and regulation of iPLA2 and highlight its functional role in mediating neurological disorders and cancer.

Structural Features of iPLA2 The group VI PLA2 (iPLA2) family comprises the following six different groups: VIA, VIB, VIC, VID, VIE and VIF. Group VIA iPLA2 contains seven to eight ankyrin repeats, a linker region and a catalytic domain [17–19]. The human group VIA iPLA2 occurs as five different splicing variants, including VIA-1(iPLA2), VIA-2(iPLA2b), VIA-3, VIA Ank-1 and VIA Ank-2 (Fig. 1). VIA-1 and VIA-2 are known to possess enzymatic activity. VIA-2 is often referred to as the long form as it has extra 59 proline-rich amino acid stretch, compared to VIA-1, a short form. VIA-2, first isolated from the p388D1 cell line, has a molecular mass of 88.6 kDa and was shown to be active only as a tetramer [20]. The active site of iPLA2b contains serine, which lies within a lipase consensus sequence (Gly-X-Ser519-X-Gly) [19]. A study showed that an iPLA2 deletion mutant lacking the ankyrin repeats, but retaining its catalytic domain, loses its activity, indicating the requirement of ankyrin repeats for the iPLA2 activity [19]. Ankyrin repeats are suggested to regulate the enzyme by mediating protein–protein interaction and oligomerization of the enzyme [21]. Some studies showed that Ank-1 and Ank-2, truncated iPLA2b proteins, can interact with full-length iPLA2b and regulate the catalytic activity in a dominant-negative manner [22–24] (Fig. 2). Molecular dynamics simulations, guided by deuterium Fig. 1 Schematic representation of the multiple human group VIA iPLA2 isoforms (The simplified structure, number of amino acids (AAs) and molecular mass of group VIA iPLA2 variant are shown in this figure)

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exchange experimental studies, have shed light on deeper understanding of the binding pocket of iPLA2. Mouchlis et al. [25] demonstrated that the binding pocket of iPLA2 comprises 45% of the hydrophobic region, 30% of the hydrophilic region and 25% of a mixed character region. The hydrophobic region contains amino acid residues such as Val548, Phe549, Phe644, Val721, Phe722, Leu770 and Leu778. The hydrophilic region is further divided into 10% of H-bond donor region and 20% of H-bond acceptor region containing amino acid residues such as Asp484, Gly486, Gly487, Lys489, Ser519, Asp652, Asn658, Lys725, Lys729 and Asp733. A study on binding of the phospholipid substrate 1-palmitoyl-2-arachidonoyl-snglycero-3-phosphocholine (PAPC) to the binding pocket of iPLA2 using induced fit docking and steered molecular dynamics simulations demonstrated the interaction of fatty acid tails of PAPC with the iPLA2 binding pocket residues such as Val548, Phe549, Phe643, Phe644, Val721, Phe722, Leu770 and Leu778 [25].

Regulation of iPLA2 Activity Hydrogen Peroxide (H2O2) H2O2 is a cellular oxidant generated by the action of superoxide dismutase on superoxide anions. Enhanced H2O2 level causes several cellular responses such as a change in gene expression, an increase in intracellular Ca2? levels and activation of protein kinase C (PKC) and mitogen-activated protein kinases (MAPK) [26]. H2O2 induces oxidative stress and causes cellular toxicity that accelerates apoptosis and cell death [27]. Reactive oxidative species enhance the release of various free fatty acids, including arachidonic acid, which causes oxidative stress in the cells [27]. iPLA2 catalyses the release of arachidonic acid from the sn-2 position of phospholipids, making the free fatty acids accessible to prostaglandin synthesis [1].

Role of Calcium-Independent Phospholipase A2 VIA in Mediating Neurological Disorder and Cancer Fig. 2 Structure of group VIA2 iPLA2 (ankyrin repeats are shown in grey. The insertion is shown in black. The ATPbinding domain is shown in green. The serine lipase consensus sequence is shown in yellow. The bipartite nuclear localization sequence is shown in pink. Calmodulin-binding motifs are shown in blue. Caspase cleavage sites are shown in black frames)

H2O2-dependent hyperoxidation of peroxiredoxin 6 plays a role in cellular toxicity via upregulation of iPLA2 activity [28]. Therefore, H2O2-induced iPLA2 activation is of particular interest in oxidative stress-induced cellular damage [29]. Oxidative stress is a major factor underlying cellular damage in a number of neurodegenerative disorders, and iPLA2 mediates H2O2-induced human neural cell death [30]. However, the molecular mechanism behind H2O2induced iPLA2 activity and its role in neurodegeneration are not yet fully understood. Therefore, further studies using different cells from the brain are needed to unravel the cellular regulations mediated via the interaction between H2O2 and iPLA2 activity. ATP iPLA2 contains glycine-rich, nucleotide-binding motif (GXGXXG) before the catalytic active site. This motif is homologous to common nucleotide-binding motifs of

various kinases (e.g. sphingosine kinase) and other ATPand GTP-binding proteins [31–33]. This feature allows ATP to stabilise and protect the enzyme from loss of its activity in vitro [20, 34]. However, there is no direct evidence for defining the regulatory interplay between iPLA2 and ATP in an intact cell. Oligomerization iPLA2 can form a large oligomeric complex as shown by the association of the 85-kDa iPLA2 with an apparent molecular weight of 250–350 kDa protein [20]. This is likely due to oligomerization of active iPLA2 via interactions between ankyrin repeats [19]. Ankyrin repeats have been also found in several proteins facilitating their interactions with other proteins [35]. Several cells express truncated iPLA2 protein lacking the catalytic domain but containing the ankyrin repeats domain. Studies found that co-transfection of truncated iPLA2, having ankyrin repeats

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domain but not the catalytic domain, with full-length iPLA2 enzyme leads to reduction in activity of the fulllength iPLA2 enzyme [23, 36]. These observations provide a significant support for the hypothesis that ankyrin repeats are required for the regulation of iPLA2 activity via enabling oligomerization of iPLA2 [22, 36, 37]. Earlier studies have reported that oxidants could induce oligomerization of iPLA2 via oxidation of sulfhydryl groups in the N-terminal ankyrin repeats domain and suppress its activity by altering its subcellular localization [22]. Oligomerization induced by ATP or ADP has also been reported in iPLA-1, a homolog of iPLA2b in Caenorhabditis elegans. Unlike oxidants, oligomerization induced by ATP enhanced the enzyme activity by promoting the self-assembly of iPLA-1 into larger molecular weight complexes [38]. These studies clearly suggest that oligomerization of iPLA2 via different mechanisms has a significant impact on the enzyme activity and localization. Ca21-calmodulin iPLA2 contains two calmodulin-binding motifs (IRKGQGNKVKKLSI and AWSEMVGIQYFR) near its C terminus, and these allow the enzyme to bind calmodulin in a calcium-dependent manner. In the presence of calcium, calmodulin binds to iPLA2 and forms a catalytically inactive complex. In the absence of calcium, CaMKIIb activates iPLA2b by relieving its tonic inhibition via displacing calmodulin from iPLA2b [39]. Thus, depletion of Ca2? stores during the regular mechanism of calcium signalling activates iPLA2 in vascular myocytes, human granulocytes and pancreatic islet cells [40]. Regulation of calcium concentration by the interaction of CaMKIIb and iPLA2b also plays a very important role in insulin secretion [41]. Phosphorylation Although no phosphorylation consensus sequence has been found in iPLA2 [18, 19, 23, 42], various studies suggest the role of phosphorylation of other proteins in regulating the activity of iPLA2, including PKC and p38 MAP kinases [43–49]. The neutrophil NADPH oxidase (NOX2) is a key enzyme responsible for host immune defences through the production of reactive oxygen species. A signalling pathway leading to NOX2 activation was characterised in which iPLA2-regulated p38 MAPK activity is a key regulator of S100A8/A9 translocation via S100A9 phosphorylation [50]. Using HL-60 cells, it was demonstrated that translocation of two Ca2?-binding proteins of the S100 family, S100A8 and S100A9, is mediated by an increase in (Ca2?)i through depletion of intracellular Ca2? stores. It was further confirmed that p38 MAPK induces S100A9 phosphorylation, a prerequisite for S100 translocation.

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Using a selective inhibitor for iPLA2, it was shown that p38 MAPK-mediated S100A9 phosphorylation is dependent upon iPLA2 activity [50]. GSK3B phosphorylation reduces Tau protein phosphorylation and enhances iPLA2 activity in platelets of patients with Alzheimer’s disease (AD) [51]. Similarly, iPLA2 activity regulates phosphorylation of the serine 831 residue of the AMPA receptor GluR1 subunit in synaptosomal P2 fractions and residues Ser880/891 of GluR2/3 subunits [52]. Pharmacological Inhibitors of iPLA2 In recent years, a variety of synthetic polyfluoroketones have been developed to explore the biological role of iPLA2 [53–56]. Among the polyfluoroketones, pentafluoroethyl ketones such as FKGK11 and GK187 are considered to be a selective potent inhibitor of iPLA2 [55]. Furthermore, FKGK18, a fluoroketone inhibitor is 195-fold and [455-fold more potent for iPLA2 than other PLA2s [54]. A recent study has suggested the pharmacological role of FKGK18 in the prevention of iPLA2-mediated bcell apoptosis and diabetes [57]. There are several serine-reactive inhibitors of iPLA2 such as bromoenol lactone (BEL), methyl arachidonyl fluorophosphonate (MAFP), fatty acyl trifluoromethyl ketones and tricarbonyls [22, 42, 58–60]. Among them, BEL is considered as a selective irreversible inhibitor of iPLA2. Studies on the mechanism of inhibition have shown that binding of BEL to iPLA2 leads to production of a bromoketomethyl acid, which leads to covalent modification of cysteine residues but not the active serine site of iPLA2 [61]. Interestingly, Jenkins et al. [62] demonstrated that the S- and R-enantiomers of BEL exhibit specific inhibition of iPLA2b and iPLA2c, respectively [62]. On the other hand, deuterium exchange mass spectrometry and molecular dynamics simulation studies on the mechanism of inhibition of iPLA2 by fluoroketones have shown that fluoroketones favourably interact with the active site pocket of iPLA2 and avoid the presence of phospholipid substrates for catalysis [25]. Studies using BEL as a selective inhibitor of iPLA2 have reported decreased generation of prostaglandins and hyperalgesia at the inflammatory loci of rats [63]. Treatment with BEL causes acute loss of neurites and impairs cell body of cortical neurons [64]. A behavioural study suggested that selective inhibition of iPLA2 activity by BEL in the hippocampus region of the rat impairs the acquisition of short-term memory (STM) and long-term memory (LTM) [65]. BEL is also reported to activate p38 MAPK pathway and inhibit cell proliferation during cytostasis in prostate cancer cells [8]. These findings may provide future direction to explore the signalling mechanisms involving iPLA2 in the brain. In addition, advanced

Role of Calcium-Independent Phospholipase A2 VIA in Mediating Neurological Disorder and Cancer

technologies such as gene knock down by expression of antisense oligonucleotide, small interfering RNA and disruption of the gene encoding iPLA2VIA are effective approaches besides using synthetic inhibitors in defining the role of iPLA2 in a given cellular process [3, 66–72].

Role of iPLA2 in Neurological Disorders Impairment in Memory Acquisition Studies have shown that STM and LTM are modulated by receptors, including N-methyl-D-aspartate (NMDA) receptor, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, metabotropic glutamate receptors and muscarinic cholinergic receptors [73, 74]. Synaptic plasticity referred to as short-term potentiation (STP) and long-term potentiation (LTP) is widely considered to underlie the formation of STM and LTM. [73, 75]. Inhibition of iPLA2 in rat hippocampal slices has shown to prevent the LTP process, suggesting the critical role of iPLA2 in the initiation of LTP [76]. iPLA2 is also implicated in the role of docosahexaenoic acid (DHA) in LTP. The regulation of corticostriatal LTP is dependent on iPLA2-mediated release of DHA. Depotentiation of corticostriatal LTP is impaired by selective inhibition of iPLA2, which can be restored by DHA treatment [77]. Hippocampus, being a limbic structure, is especially important in learning and memory and is, therefore, quite sensitive to chronic stress and glucocorticoids. Overexposure to glucocorticoids, due to ageing, compromises the hippocampus through dendritic retraction [78, 79]. The physiological and pathological implications of iPLA2 in the hippocampus have been studied extensively over the years. The iPLA2c isoform has been shown to control both the functional and biochemical properties of glutamate receptors and thus affects synaptic plasticity and excitotoxic cell damage [80]. In vivo inhibition of iPLA2b using BEL or siRNA in the prefrontal cortex abolished the induction of hippocampoprefrontal cortical LTP of memory as determined by the T-maze task, indicating negative effects on spatial working memory [81].

related to neurite outgrowth and differentiation in both neurodevelopmental processes and response to neuronal injury [82]. Reduced iPLA2 and cPLA2 activity is reported in the cerebral cortex and hippocampus of people with AD, which is positively correlated with the density of neurofibrillary tangles [83–85]. Schaeffer et al. [86] demonstrated that MAFP, an inhibitor of iPLA2 and cPLA2, significantly inhibited PLA2 activity in the frontal cortex and hippocampus of rat brain, decreased total Tau protein levels and increased Tau phosphorylation at Ser(214) [86]. Increment in PLA2 activities contributes to the enhancement of production of arachidonic acid (AA), which results in LTP of Ca2?-sensitive induction in the hippocampus slices of rat brains [87]. Based on these findings, memory enhancement was clearly observed in another study [88]. Reduced PLA2 activity and increased phosphorylation of glycogen synthase kinase 3B (GSK3B) have been shown to potentiate beta-amyloid plaques and neurofibrillary tangles in AD patients [51]. In vivo experiments on AD patients treated with donepezil (an acetylcholinesterase inhibitor) showed a significant increase in iPLA2 activity and a positive correlation of iPLA2 increment with memory acquisition and retention. Parkinson’s Disease Parkinson’s disease (PD) is a common neurodegenerative disease. PD is estimated to affect approximately 2% of the population aged more than 65 years, while a total of 1.7 million PD patients (aged C55 years) live in China [89]. The PLA2G6 gene encodes iPLA2 and has been suggested to be the causative gene for autosomal recessive dystonia-parkinsonism. Beck et al. [90] reported increased brain iron deposition in iPLA2b-knockout mice [90]. Iron deposition in the brain causes PD. Patients with adult-onset, L-dopa-responsive, dystonia-parkinsonism, known as PARK14, were reported to have mutations in the PLA2G6 gene [91]. Interestingly, most of these cases showed the absence of iron depositions on MRI, which might be due to the difference in the catalytic activity of iPLA2b enzymes between the different disease phenotypes, INAD/NBIA and dystonia-parkinsonism [91–93]. Epilepsy

Alzheimer’s Disease AD is the primary cause of dementia among aged people and has no known cure. Evidence suggests that reduced activity of specific subtypes of cPLA2 and iPLA2 is an early event in AD and may contribute to memory impairment and neuropathology. As stated earlier, PLA2 activation is induced in the healthy brain during learning and memory that regulates endogenous neurogenesis. PLA2 seems to be associated with the homeostatic processes

Epilepsy is a chronic neuronal disorder that is often accompanied by muscular spasms leading to seizures and convulsions. The normal neuronal activity and neurotransmission are hampered. Temporal lobe epilepsy (TLE) is the most frequent cause of focal refractory epilepsy in adults [94]. The prevalence of schizophrenia-like symptoms in patients with TLE can range from 7% to 11% and is in fact higher than the expected prevalence of 0.5–1% in the general population [95].

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In a study conducted with a sample size of 16 patients, it was established that TLE is characterised by significantly higher calcium-independent PLA2 activity compared with normal subjects. It was also hypothesised that this increased activity may not only be restricted to epilepsy but could also be common to all psychosis-related diseases [96]. The activity of iPLA2 controls the biochemical and physical properties of neuronal membranes, affecting, for instance, receptor function and the release and reuptake of neurotransmitters [97]. Treatment options of epilepsy have recently seen the rise of inhibitors against certain enzymatic targets, such as brivaracetam (BRV). BRV is chemically related to levetiracetam (LEV) and has a strong binding affinity for the synaptic vesicle protein 2A. This affinity is tenfold higher than that of LEV. BRV is now under Phase III development for POS, but data from a Phase III trial also suggested its potential efficacy for primary generalised seizures [98]. An inhibitor-based drug against elevated iPLA2 activity in epilepsy could be a good therapeutic option to explore. Infantile Neuroaxonal Dystrophy (INAD) INAD or Seitelberger’s disease is a rare autosomal recessive neurodegenerative disorder. Since its first description [99], this disorder was commonly confused with another disease known as neurodegeneration with brain iron accumulation (NBIA), which manifested similar symptoms. Based on the common symptom of brain iron accumulation, it was initially hypothesised that both diseases had the same aetiology. When the cause for NBIA was discovered [100] to be a rare mutation in the gene pantothenate kinase 2 (PANK2), several researchers believed that INAD and NBIA were caused by the same mutation. However, a few years later, a genetic study in seven INAD families revealed [101] that there were no mutations in PANK2, hence debunking the common belief and reopening the Pandora’s box. This rare disorder was later linked to a mutation in the Ca2?-independent phospholipase A2 gene, PLA2G6 [102]. INAD is characterised by pathological axonal swelling and appearance of spheroidal bodies in the CNS. Contrasting symptomatic features between INAD and NBIA were later described [103], with a clear distinction in the age at which death occurs; for INAD, the age is usually before the age of 10 years, while for NBIA it is the third decade. The aetiology between both diseases is also shared by the fact that mutations in the PLA2G6 gene cause both INAD and, to some extent, an atypical neuroaxonal dystrophy that overlaps clinically with other forms of NBIA. Hence, PLA2G6 is not only responsible for INAD but also contributes towards the pathology of NBIA as well.

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A mutated PLA2G6 causes PLA2G6-associated neurodegeneration (PLAN) that leads to INAD and, more recently, adult-onset dystonia-parkinsonism (PARK14) [104]. PLA2G6-knockout mice exhibit progressive impairment by 1 year of age with the primary pathological occurrence of spheroidal bodies in the CNS. These knockout mice survive for a shorter time than the wild type, presumably due to progressive axonal degeneration in both central and peripheral nervous systems accompanied by cerebellar atrophy [105]. These findings are similar to the pathology of INAD in human beings, thus suggesting the fact that mutated non-functional iPLA2 is indeed the cause of INAD. Mice that harbour point mutation (G373) at an ankyrin repeat in the PLA2G6 gene show progressive motor impairment during the 7–8 weeks after birth and the symptoms lead to death by 18 weeks [106].

Role of iPLA2 in Cancer Increased activity and expression of several PLA2 isoforms in various human cancers suggest its involvement in the development of tumour and also provide future direction for studies concerning whether these enzymes will be a target for anticancer drugs. The role of iPLA2 in tumourigenesis is not well studied compared with cPLA2 and sPLA2 [107]. However, several studies have indicated the role of iPLA2 in cell proliferation, phospholipid remodelling, signal transduction and apoptosis. Studies have also demonstrated that upregulation of iPLA2 contributes to tumourigenesis. Recently, Yun et al. [9] reported that loss of presenilins induces lung cancer development via upregulation of iPLA2 activity by reducing c-secretase. It must be noted that presenilins are the enzymatic components of c-secretase complex that cleaves amyloid precursor proteins such as Notch and b-catenin, which play critical roles in the development of AD and cancer cell growth [9]. Another study reported that peroxiredoxin-6-overexpressing nude mice exhibited enhanced lung tumour growth via increased iPLA2 and glutathione peroxidase activities [108]. Further studies demonstrated that inhibition of iPLA2 activity or expression suppresses cancer cell proliferation. Li et al. [109] reported that tumourigenesis and ascites formation were reduced in epithelial ovarian cancer cells injected into iPLA2b-knockout mice by [50% and were reduced further (up to 95%) when iPLA2b levels of epithelial ovarian cancer cell line were decreased by shRNA. Inhibition of iPLA2 activity induced cytostasis of prostate cancer cells via activation of p38 MAPK signalling pathway [8]. A study on human colorectal carcinoma cell (Caco-2) showed that treatment with an antisense oligonucleotide against iPLA2b decreased AA mobilisation and PGE2 production, leading to the inhibition of Caco-2 cell proliferation [110]. Elevated iPLA2

Role of Calcium-Independent Phospholipase A2 VIA in Mediating Neurological Disorder and Cancer

signalling activity has also been associated with human melanomas. Significant associations have been demonstrated between variants of iPLA2 and the propensity to develop moles on the skin, which increases melanoma risk [111]. A genome-wide association study with 4107 subjects revealed that PLA2G6 gene was associated with mole counts and melanoma risk [111]. It has also been shown that a majority of human melanoma cell lines (M10, M14, SKMEL28, SK-MEL93, 243MEL, 1074MEL, OCM-1 and COLO38) expressed, at mRNA and protein levels, high level of iPLA2 [112]. These studies suggest that iPLA2b represents a potential target for the treatment of various types of cancer. However, the role of PLA2 in the mechanism of carcinogenesis is still considered to be diverse and somewhat controversial. This is because fatty acids and lysophospholipids generated by PLA2 are further metabolised into different species, all of which regulate the cell growth and also cell death in various models. Thus, a controversy still exists as to which lipids are more important to cell death and which are more important to cell growth.

Conclusions Over the past decade, there has been a growing interest in identifying the links between iPLA2 dysregulation and neurological disorders. Exploring the functions of lipid signalling due to the activation of iPLA2 in the pathogenesis of several diseases may facilitate the discovery of novel pathways that can potentially help find a new drug target. This short review is an effort to provide the current understanding on the regulation of iPLA2 and a new direction for addressing the key role of iPLA2 in neurological disorders and cancer.

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