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Inhibition of cytosolic phospholipase A2 alpha increases chemosensitivity in cervical carcinoma through suppressing β-catenin signaling.

ABSTRACT: Cytosolic phospholipase A2alpha (cPLA2α) is a key mediator of tumorigenesis. In this study, by using a combination of pharmacological and genetic approaches in cell models and patient samples, we identify cPLA2α as a selective target to increase chemosensitivity in cervical cancer. We found that transcript and protein levels of cPLA2α but not other forms of cPLA2 (e.g., cPLA2β and cPLA2αδ) were consistently increased in all tested malignant cervical cancer cells and tissues compared to normal counterparts, suggesting that cPLA2α upregulation is a common feature in cervical cancer. We further found that promoting growth and survival rather than invasion were the predominant roles of cPLA2α on cervical cancer. In addition, chemotherapeutic agents achieved ~100% inhibition efficacy in cPLA2α-depleted cervical cancer cells, demonstrating the important role of cPLA2α in chemoresistance. Importantly, we identify that β-catenin is critically involved in the molecular mechanism of cPLA2α's action in cervical cancer. In summary, our work demonstrates the multiple essential roles of cPLA2α in cervical cancer, particularly in chemoresistance, via a β-catenin-dependent manner. Our work also suggests that targeting cPLA2α has a therapeutic value in overcoming chemoresistance in cervical cancer or other cPLA2α-regulated cancers.

SUBMITTER: Xu H

PROVIDER: S-EPMC6605985 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cytosolic phospholipase A2 alpha regulates TLR signaling and migration in metastatic 4T1 cells

Project description:We aimed at characterizing the response to reduced cPLA2α activity in metastatic versus non-metastatic cells. We employed an isogenic murine cell line pair displaying metastatic (4T1) and non-metastatic (67NR) phenotype to investigate the role of cPLA2α on migration. Further, we elucidate the effect of reduced cPLA2α activity on global gene expression in the metastatic cell line We found that cPLA2α inhibition may inhibit metastasis through an anti-migratory effect, possibly involving Toll-like receptor signaling and type I interferons

2019-09-26 | GSE138026 | GEO

Cytosolic Phospholipase A2 Alpha Regulates TLR Signaling and Migration in Metastatic 4T1 Cells.

Project description:Metastatic disease is the leading cause of death in breast cancer patients. Disrupting the cancer cell's ability to migrate may be a strategy for hindering metastasis. Cytosolic phospholipase A2 ? (cPLA2?), along with downstream proinflammatory and promigratory metabolites, has been implicated in several aspects of tumorigenesis, as well as metastasis, in various types of cancer. In this study, we aim to characterize the response to reduced cPLA2? activity in metastatic versus non-metastatic cells. We employ an isogenic murine cell line pair displaying metastatic (4T1) and non-metastatic (67NR) phenotype to investigate the role of cPLA2? on migration. Furthermore, we elucidate the effect of reduced cPLA2? activity on global gene expression in the metastatic cell line. Enzyme inhibition is achieved by using a competitive pharmacological inhibitor, cPLA2? inhibitor X (CIX). Our data show that 4T1 expresses significantly higher cPLA2? levels as compared to 67NR, and the two cell lines show different sensitivity to the CIX treatment with regards to metabolism and proliferation. Inhibition of cPLA2? at nontoxic concentrations attenuates migration of highly metastatic 4T1 cells, but not non-metastatic 67NR cells. Gene expression analysis indicates that processes such as interferon type I (IFN-I) signaling and cell cycle regulation are key processes regulated by cPLA2a in metastatic 4T1 cells, supporting the findings from the biological assays. This study demonstrates that two isogenic cancer cell lines with different metastatic potential respond differently to reduced cPLA2? activity. In conclusion, we argue that cPLA2? is a potential therapeutic target in cancer and that enzyme inhibition may inhibit metastasis through an anti-migratory mechanism, possibly involving Toll-like receptor signaling and type I interferons.

| S-EPMC6801560 | biostudies-literature

Cytosolic phospholipase A2? increases proliferation and de-differentiation of human renal tubular epithelial cells.

Project description:The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2?) enzyme controls the release of arachidonic acid from membrane bound phospholipids and is the rate-limiting step in production of eicosanoids. A variety of different kidney injuries activate cPLA2?, therefore we hypothesized that cPLA2? activity would regulate pathologic processes in HK-2 cells, a human renal tubular epithelial cell line, by regulating cell phenotype and proliferation. In two lentiviral cPLA2?-silenced knockdowns, we observed decreased proliferation and increased apoptosis compared to control HK-2 cells. cPLA2?-silenced cells also demonstrated an altered morphology, had increased expression E-cadherin, and decreased expression of Ncadherin. Increased levels of E-cadherin were associated with increased promoter activity and decreased levels of SNAIL1, SNAIL2, and ZEB1, transcriptional repressors of E-cadherin expression. Addition of exogenous arachidonic acid, but not PGE2, reversed the phenotypic changes in cPLA2?-silenced cells. These data suggest that cPLA2? may play a key role in renal repair after injury through a PGE2-independent mechanism.

| S-EPMC5099119 | biostudies-literature

Cytosolic phospholipase A2 modulates TLR2 signaling in synoviocytes.

Project description:Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis leading to destruction of cartilage and bone. PLA2 enzymes are key players in inflammation regulating the release of unsaturated fatty acids such as arachidonic acid (AA), a precursor of pro-inflammatory eicosanoids. Several lines of evidence point to toll-like receptors (TLRs) as drivers of synovitis and joint destruction in RA. However, few studies have addressed the implication of PLA2 activity downstream TLR activation in the synovium. Here, we aimed to characterize PLA2 enzyme involvement in TLR2-induced signaling in synovial fibroblast-like cells. TLRs1-7 and a range of sPLA2, iPLA2 and cPLA2 enzymes were found to be transcriptionally expressed in cultured synoviocytes. Activation of TLR2/1 and TLR2/6 led to phosphorylation of cPLA2α at Ser505, and induced AA release and PGE2 production; effects that were attenuated by cPLA2α inhibitors. In contrast, sPLA2 inhibitors did not affect AA or PGE2 release. cPLA2α inhibitors furthermore attenuated TLR-induced expression of IL-6, IL-8 and COX2. COX1/2 inhibitors attenuated TLR2/6-induced IL-6 transcription and protein production comparable to cPLA2α inhibition. Moreover, exogenously PGE2 added alone induced IL-6 production and completely rescued IL-6 transcription when added simultaneously with FSL-1 in the presence of a cPLA2α inhibitor. Our results demonstrate for the first time that cPLA2α is involved in TLR2/1- and TLR2/6-induced AA release, PGE2 production and pro-inflammatory cytokine expression in synoviocytes, possibly through COX/PGE2-dependent pathways. These findings expand our understanding of cPLA2α as a modulator of inflammatory molecular mechanisms in chronic diseases such as RA.

| S-EPMC4404349 | biostudies-literature

Cytosolic phospholipase A2 alpha inhibition prevents neuronal NMDA receptor-stimulated arachidonic acid mobilization and prostaglandin production but not subsequent cell death.

Project description:Phospholipase A(2) (PLA(2)) enzymes encompass a superfamily of at least 13 extracellular and intracellular esterases that hydrolyze the sn-2 fatty acyl bonds of phospholipids to yield fatty acids and lysophospholipids. The purpose of this study was to characterize which phospholipase paralog regulates NMDA receptor-mediated arachidonic acid (AA) release. Using mixed cortical cell cultures containing both neurons and astrocytes, we found that [(3)H]-AA released into the extracellular medium following NMDA receptor stimulation (100 microM) increased with time and was completely prevented by the addition of the NMDA receptor antagonist MK-801 (10 microM) or by removal of extracellular Ca(2+). Neither diacylglycerol lipase inhibition (RHC-80267; 10 microM) nor selective inhibition of Ca(2+)-independent PLA(2) [bromoenol lactone (BEL); 10 microM] alone had an effect on NMDA receptor-stimulated release of [(3)H]-AA. Release was prevented by methyl arachidonyl fluorophosphonate (MAFP) (5 microM) and AACOCF(3) (1 microM), inhibitors of both cytosolic PLA(2) (cPLA(2)) and Ca(2+)-independent PLA(2) isozymes. This inhibition effectively translated to block of NMDA-induced prostaglandin (PG) production. An inhibitor of p38MAPK, SB 203580 (7.5 microM), also significantly reduced NMDA-induced PG production providing suggestive evidence for the role of cPLA(2)alpha. Its involvement in release was confirmed using cultures derived from mice deficient in cPLA(2)alpha, which failed to produce PGs in response to NMDA receptor stimulation. Interestingly, neither MAFP, AACOCF(3) nor cultures derived from cPLA(2)alpha null mutant animals showed any protection against NMDA-mediated neurotoxicity, indicating that inhibition of this enzyme may not be a viable protective strategy in disorders of the cortex involving over-activation of the NMDA receptor.

| S-EPMC2582587 | biostudies-literature

PARP inhibition in vivo blocks alcohol-induced brain neurodegeneration and neuroinflammatory cytosolic phospholipase A2 elevations.

Project description:Chronic alcoholism promotes brain damage that impairs memory and cognition. High binge alcohol levels in adult rats also cause substantial neurodamage to memory-linked regions, notably, the hippocampus (HC) and entorhinal cortex (ECX). Concurrent with neurodegeneration, alcohol elevates poly (ADP-ribose) polymerase-1 (PARP-1) and cytosolic phospholipase A2 (cPLA2) levels. PARP-1 triggers necrosis when excessively activated, while cPLA2 liberates neuroinflammatory ω-6 arachidonic acid. Inhibitors of PARP exert in vitro neuroprotection while suppressing cPLA2 elevations in alcohol-treated HC-ECX slice cultures. Here, we examined in vivo neuroprotection and cPLA2 suppression by the PARP inhibitor, veliparib, in a recognized adult rat model of alcohol-binging. Adult male rats received Vanilla Ensure containing alcohol (ethanol, 7.1 ± 0.3 g/kg/day), or control (dextrose) ± veliparib (25 mg/kg/day), by gavage 3x daily for 4 days. Rats were sacrificed on the morning after the final binge. HC and ECX neurodegeneration was assessed in fixed sections by Fluoro-Jade B (FJB) staining. Dorsal HC, ventral HC, and ECX cPLA2 levels were quantified by immunoblotting. Like other studies using this model, alcohol binges elevated FJB staining in the HC (dentate gyrus) and ECX, indicating neurodegeneration. Veliparib co-treatment significantly reduced dentate gyrus and ECX neurodegeneration by 79% and 66%, respectively. Alcohol binges increased cPLA2 in the ventral HC by 34% and ECX by 72%, which veliparib co-treatment largely prevented. Dorsal HC cPLA2 levels remained unaffected by alcohol binges, consistent with negligible FJB staining in this brain region. These in vivo results support an emerging key role for PARP in binge alcohol-induced neurodegeneration and cPLA2-related neuroinflammation.

| S-EPMC6760246 | biostudies-literature

Cytosolic phospholipase A2 alpha/arachidonic acid signaling mediates depolarization-induced suppression of excitation in the cerebellum.

Project description:BackgroundDepolarization-induced suppression of excitation (DSE) at parallel fiber-Purkinje cell synapse is an endocannabinoid-mediated short-term retrograde plasticity. Intracellular Ca(2+) elevation is critical for the endocannabinoid production and DSE. Nevertheless, how elevated Ca(2+) leads to DSE is unclear.Methodology/principal findingsWe utilized cytosolic phospholipase A(2) alpha (cPLA(2)α) knock-out mice and whole-cell patch clamp in cerebellar slices to observed the action of cPLA(2)α/arachidonic acid signaling on DSE at parallel fiber-Purkinje cell synapse. Our data showed that DSE was significantly inhibited in cPLA(2)α knock-out mice, which was rescued by arachidonic acid. The degradation enzyme of 2-arachidonoylglycerol (2-AG), monoacylglycerol lipase (MAGL), blocked DSE, while another catabolism enzyme for N-arachidonoylethanolamine (AEA), fatty acid amide hydrolase (FAAH), did not affect DSE. These results suggested that 2-AG is responsible for DSE in Purkinje cells. Co-application of paxilline reversed the blockade of DSE by internal K(+), indicating that large conductance Ca(2+)-activated potassium channel (BK) is sufficient to inhibit cPLA(2)α/arachidonic acid-mediated DSE. In addition, we showed that the release of 2-AG was independent of soluble NSF attachment protein receptor (SNARE), protein kinase C and protein kinase A.Conclusions/significanceOur data first showed that cPLA(2)α/arachidonic acid/2-AG signaling pathway mediates DSE at parallel fiber-Purkinje cell synapse.

| S-EPMC3425552 | biostudies-literature

Next Generation Thiazolyl Ketone Inhibitors of Cytosolic Phospholipase A2 α: from Synthesis to Chemotherapeutic Mechanism of Action

Project description:Eicosanoids participate in the pathologies of inflammation and carcinogenesis and limiting their production by inhibiting group IVA cytosolic phospholipase A2 (cPLA2α) is a potential approach to cancer treatment. Here we report the synthesis of a new generation of thiazolyl ketone inhibitors of cPLA2α starting from compound GK470 (AVX235), and the discovery of a more potent and selective lead, GK420 (AVX420), with significant chemotherapeutic properties. A cancer cell line screen revealed the selective growth inhibitory effects of AVX420 in acute leukemias, uncovering a novel function of cPLA2α to promote cancer cell survival during oxidative stress by epigenetic control of tumour suppressor gene transcription. Moreover, we showed that in sensitive cells, AVX420 increased intracellular reactive oxygen species (ROS) and instigated a transcriptional response resulting in cell death. Our study suggests AVX420 has the potential to treat acute leukemias, and other cancers with specific adaptations to a high ROS burden.

2024-11-19 | GSE251999 | GEO

Inhibition of human cytosolic phospholipase A2 by human annexin V.

Project description:The ability of annexins, particularly annexin 1 (lipocortin 1), to inhibit phospholipase A2 (PLA2) is well known and a substrate depletion mechanism is now widely accepted as the explanation for most inhibitory studies. However, there are only a very limited number of reported studies involving annexins and the high-molecular-mass cytosolic PLA2 (cPLA2). In this study we have examined the effect of human recombinant annexin V, a potentially abundant cytosolic protein, on the ability of human recombinant cPLA2 to hydrolyse a variety of phospholipid substrates. The results show clearly that, under the conditions of our study, annexin V can inhibit cPLA2 activity by a mechanism of substrate depletion and that this inhibition is dependent on the nature of the phospholipids and the concentration of Ca2+ ions in the assay. The hydrolysis of 1-stearoyl 2-arachidonyl phosphatidylcholine by cPLA2 was not significantly affected by annexin V over a range of Ca2+ concentrations (1 microM-2.5 mM), a result that presumably reflects the zwitterionic nature of the phospholipid and the known inability of annexins to bind to such interfaces. In contrast, the hydrolysis of dioleoyl phosphatidylglycerol, which is an effective anionic phospholipid substrate for this enzyme, and more significantly that of 1-stearoyl 2-arachidonyl phosphatidic acid, were readily inhibited by annexin V, although these effects were Ca2+-dependent. The Ca2+ concentrations required for inhibition in the assay system in vitro are greater than those associated with Ca2+-stimulated events within the cell, suggesting that a role for annexin V in regulating cPLA2 activity might not involve a substrate depletion mechanism in vivo unless factors in addition to Ca2+ and phospholipids contribute to the binding of annexin V to cell membranes.

| S-EPMC1219053 | biostudies-other

Study of the role of cytosolic phospholipase A2 alpha in eicosanoid generation and thymocyte maturation in the thymus.

Project description:The thymus is a primary lymphoid organ, home of maturation and selection of thymocytes for generation of functional T-cells. Multiple factors are involved throughout the different stages of the maturation process to tightly regulate T-cell production. The metabolism of arachidonic acid by cyclooxygenases, lipoxygenases and specific isomerases generates eicosanoids, lipid mediators capable of triggering cellular responses. In this study, we determined the profile of expression of the eicosanoids present in the mouse thymus at different stages of thymocyte development. As the group IVA cytosolic phospholipase A2 (cPLA2?) catalyzes the hydrolysis of phospholipids, thereby generating arachidonic acid, we further verified its contribution by including cPLA2? deficient mice to our investigations. We found that a vast array of eicosanoids is expressed in the thymus, which expression is substantially modulated through thymocyte development. The cPLA2? was dispensable in the generation of most eicosanoids in the thymus and consistently, the ablation of the cPLA2? gene in mouse thymus and the culture of thymuses from human newborns in presence of the cPLA2? inhibitor pyrrophenone did not impact thymocyte maturation. This study provides information on the eicosanoid repertoire present during thymocyte development and suggests that thymocyte maturation can occur independently of cPLA2?.

| S-EPMC4430275 | biostudies-literature

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