scholarly journals Phospholipase A2 Drives Tumorigenesis and Cancer Aggressiveness through Its Interaction with Annexin A1

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1472
Author(s):  
Lara Vecchi ◽  
Thaise Gonçalves Araújo ◽  
Fernanda Van Petten de Vasconcelos Azevedo ◽  
Sara Teixeria Soares Mota ◽  
Veridiana de Melo Rodrigues Ávila ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Immune Evasion ◽  
Annexin A1 ◽  
Cancer Aggressiveness ◽  
Inhibitory Molecule ◽  
Cox 2 ◽  
Metabolizing Enzyme ◽  
Cox 1 ◽  
New Strategies

Phospholipids are suggested to drive tumorigenesis through their essential role in inflammation. Phospholipase A2 (PLA2) is a phospholipid metabolizing enzyme that releases free fatty acids, mostly arachidonic acid, and lysophospholipids, which contribute to the development of the tumor microenvironment (TME), promoting immune evasion, angiogenesis, tumor growth, and invasiveness. The mechanisms mediated by PLA2 are not fully understood, especially because an important inhibitory molecule, Annexin A1, is present in the TME but does not exert its action. Here, we will discuss how Annexin A1 in cancer does not inhibit PLA2 leading to both pro-inflammatory and pro-tumoral signaling pathways. Moreover, Annexin A1 promotes the release of cancer-derived exosomes, which also lead to the enrichment of PLA2 and COX-1 and COX-2 enzymes, contributing to TME formation. In this review, we aim to describe the role of PLA2 in the establishment of TME, focusing on cancer-derived exosomes, and modulatory activities of Annexin A1. Unraveling how these proteins interact in the cancer context can reveal new strategies for the treatment of different tumors. We will also describe the possible strategies to inhibit PLA2 and the approaches that could be used in order to resume the anti-PLA2 function of Annexin A1.

scholarly journals Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension

2008 ◽  
Vol 295 (5) ◽  
pp. G953-G964 ◽  
Author(s):  
N. J. Skill ◽  
N. G. Theodorakis ◽  
Y. N. Wang ◽  
J. M. Wu ◽  
E. M. Redmond ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
The United States ◽  
Portal Vein Ligation ◽  
Wild Type ◽  
Sham Surgery ◽  
Cox 2 ◽  
Hemodynamic Measurements ◽  
Cyclooxygenase Isoforms ◽  
Cox 1

Portal hypertension (PHT) is a common complication of liver cirrhosis and significantly increases morbidity and mortality. Abrogation of PHT using NSAIDs has demonstrated that prostacyclin (PGI2), a direct downstream metabolic product of cyclooxygenase (COX) activity, is an important mediator in the development of experimental and clinical PHT. However, the role of COX isoforms in PGI2 biosynthesis and PHT is not fully understood. Prehepatic PHT was induced by portal vein ligation (PVL) in wild-type, COX-1−/−, and COX-2−/− mice treated with and without COX-2 (NS398) or COX-1 (SC560) inhibitors. Hemodynamic measurements and PGI2 biosynthesis were determined 1–7 days after PVL or sham surgery. Gene deletion or pharmacological inhibition of COX-1 or COX-2 attenuated but did not ameliorate PGI2 biosynthesis after PVL or prevent PHT. In contrast, treatment of COX-1−/− mice with NS398 or COX-2−/− mice with SC560 restricted PGI2 biosynthesis and abrogated the development of PHT following PVL. In conclusion, either COX-1 or COX-2 can mediate elevated PGI2 biosynthesis and the development of experimental prehepatic PHT. Consequently, PGI2 rather then COX-selective drugs are indicated in the treatment of PHT. Identification of additional target sites downstream of COX may benefit the >27,000 patients whom die annually from cirrhosis in the United States alone.

Role of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) derived prostaglandins (PG) in adaptive cytoprotection induced by mild stress

1998 ◽  
Vol 114 ◽  
pp. A82
Author(s):  
T. Brzozowski ◽  
P.C. Konturek ◽  
R. Pajdo ◽  
N. Nagraba ◽  
A. Szczeklik ◽  
...  
Keyword(s):  
Cyclooxygenase 2 ◽  
Mild Stress ◽  
Adaptive Cytoprotection ◽  
Cyclooxygenase 1 ◽  
Cox 2 ◽  
Cox 1

A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats

2002 ◽  
Vol 283 (4) ◽  
pp. R862-R868 ◽  
Author(s):  
F. Lugarini ◽  
B. J. Hrupka ◽  
G. J. Schwartz ◽  
C. R. Plata-Salaman ◽  
W. Langhans
Keyword(s):  
Cerebrospinal Fluid ◽  
Cyclooxygenase 2 ◽  
Major Metabolite ◽  
Time Dependent ◽  
Selective Inhibitors ◽  
Cox 2 ◽  
Cox 1

Because nonselective cycloooxygenase (COX) inhibition attenuated anorexia after lipopolysaccharide (LPS) administration, we tested the ability of resveratrol (2.5, 10, and 40 mg/kg) and NS-398 (2.5, 10, and 40 mg/kg), selective inhibitors of the two COX isoforms COX-1 and -2, respectively, to attenuate LPS (100 μg/kg ip)-induced anorexia. NS-398 (10 and 40 mg/kg) administered with LPS at lights out attenuated LPS-induced anorexia, whereas resveratrol at all doses tested did not. Because prostaglandin (PG) E2 is considered the major metabolite synthesized by COX, we measured plasma and cerebrospinal fluid (CSF) PGE2levels after LPS administration. LPS induced a time-dependent increase of PGE2 in CSF but not in plasma. NS-398 (5, 10, and 40 mg/kg) blocked the LPS-induced increase in CSF PGE2, whereas resveratrol (10 mg/kg) did not. These results support a role of COX-2 in mediating the anorectic response to peripheral LPS and point at PGE2 as a potential neuromodulator involved in this response.

COX-2 inhibition prevents downregulation of key renal water and sodium transport proteins in response to bilateral ureteral obstruction

2005 ◽  
Vol 289 (2) ◽  
pp. F322-F333 ◽  
Author(s):  
Rikke Nørregaard ◽  
Boye L. Jensen ◽  
Chunling Li ◽  
Weidong Wang ◽  
Mark A. Knepper ◽  
...  
Keyword(s):  
Sodium Transport ◽  
Ureteral Obstruction ◽  
Transport Proteins ◽  
Outer Medulla ◽  
Fold Induction ◽  
Cox 2 ◽  
Type 3 ◽  
Sodium Handling ◽  
Cox 1

Bilateral ureteral obstruction (BUO) is associated with marked changes in the expression of renal aquaporins (AQPs) and sodium transport proteins. To examine the role of prostaglandin in this response, we investigated whether 24-h BUO changed the expression of cyclooxygenases (COX-1 and -2) in the kidney and tested the effect of the selective COX-2 inhibitor parecoxib (5 mg·kg−1·day−1 via osmotic minipumps) on AQPs and sodium transport. Sham and BUO kidneys were analyzed by semiquantitative immunoblotting, and a subset of kidneys was perfusion fixed for immunocytochemistry. BUO caused a significant 14-fold induction of inner medullary COX-2 (14.40 ± 1.8 vs. 1.0 ± 0.4, n = 6; P < 0.0001) and a reduction in medullary tissue osmolality, whereas COX-1 did not change. Immunohistochemistry confirmed increased COX-2 labeling associated with medullary interstitial cells. COX isoforms did not change in cortex/outer medulla after 24-h BUO. In BUO kidneys, inner medullary AQP2 expression was reduced, and this decrease was prevented by parecoxib. In the inner stripe of outer medulla, the type 3 Na+/H+ exchanger (NHE3) and apical Na+-K+-2Cl− cotransporter (BSC-1) were significantly reduced by BUO, and this decrease was significantly attenuated by parecoxib. Immunohistochemistry for AQP2, NHE3, and BSC-1 confirmed the effect of parecoxib. Parecoxib had no significant effect on the Na-K-ATPase α1-subunit, type II Na-Pi cotransporter, or AQP3. In conclusion, acute BUO leads to marked upregulation of COX-2 in inner medulla and selective COX-2 inhibition prevents dysregulation of AQP2, BSC-1, and NHE3 in response to BUO. These data indicate that COX-2 may be an important factor contributing to the impaired renal water and sodium handling in response to BUO.

scholarly journals Crotalus durissus ruruima Snake Venom and a Phospholipase A2 Isolated from This Venom Elicit Macrophages to Form Lipid Droplets and Synthesize Inflammatory Lipid Mediators

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ana Eduarda Zulim de Carvalho ◽  
Karina Giannotti ◽  
Elbio Leiguez Junior ◽  
Márcio Matsubara ◽  
Maria Cristina Dos Santos ◽  
...  
Keyword(s):  
Snake Venom ◽  
Inflammatory Mediators ◽  
Lipid Droplets ◽  
Lipid Mediators ◽  
Immunological Responses ◽  
Inflammatory Stimuli ◽  
Cox 2 ◽  
Crotalus Durissus ◽  
Cox 1

Viper snake Crotalus durissus ruruima (Cdr) is a subspecies found in northern area of Brazil. Among the snakes of Crotalus genus subspecies, the venom of Cdr presents highest level of crotoxin, which is the major component of Crotalus snake venoms, formed by two subunits (crotapotin and a phospholipase A2 named CBr) and presents potent neurotoxic activity. Curiously, the venom of C. d. ruruima (CdrV) is better neutralized by antibothropic than by anticrotalic serum, strongly suggesting that this venom has similarities with venom of Bothrops genus snakes with regard to the ability to induce inflammation. Macrophages are cells with a central role in inflammatory and immunological responses. Upon inflammatory stimuli, these cells exhibit increased numbers of lipid droplets, which are key organelles in the synthesis and release of inflammatory mediators. However, the effects of CdrV and CBr in macrophage functions are unknown. We herein investigated the ability of CdrV and CBr to activate macrophages with focus on the formation of lipid droplets (LDs), synthesis of lipid mediators, and mechanisms involved in these effects. The involvement of LDs in PGE2 biosynthesis was also assessed. Stimulation of murine macrophages with CdrV and CBr induced an increased number of LDs and release of prostanoids (PGE2, PGD2, and TXB2). Neither CdrV nor CBr induced the expression of COX-1 and COX-2 by macrophages. LDs induced by both CdrV and CBr are associated to PLIN2 recruitment and expression and were shown to be dependent on COX-1, but not COX-2 activity. Moreover, PGE2 colocalized to CdrV- and CBr-induced LDs, revealing the role of these organelles as sites for the synthesis of prostanoids. These results evidence, for the first time, the ability of a whole snake venom to induce formation of LDs and the potential role of these organelles for the production of inflammatory mediators during envenomation by Crotalus snakes.

scholarly journals The role of cyclooxygenase inhibitors in lipopolysaccharide-induced hypophagia in chicken

2018 ◽  
Vol 60 (No. 8) ◽  
pp. 342-350 ◽  
Author(s):  
M. Zendehdel ◽  
A. Baghbanzadeh ◽  
B. Yeganeh ◽  
S. Hassanpour
Keyword(s):  
Feed Intake ◽  
Cyclooxygenase Inhibitors ◽  
Post Injection ◽  
Cyclooxygenase Inhibitor ◽  
Guide Cannula ◽  
Treatment Groups ◽  
Cyclooxygenase 1 ◽  
Cox 2 ◽  
Cox 1

Previous studies showed that cyclooxygenase 1 (COX) enzyme has an important role in lipopolysaccharide (LPS)-induced hypophagia in mammals but the effect of COX on LPS-induced hypophagia has not been studied in avian species. The current study was designed to investigate the effects of Indomethacin, a non-selective cyclooxygenase inhibitor, Aspirin (irreversible cyclooxygenase inhibitor), Piroxicam (a selective COX-1 inhibitor), and Celecoxib (a selective COX-2 inhibitor) on LPS-induced hypophagia in 3-h food-deprived (FD<sub>3</sub>) cockerels. One hundred and sixty ROSS 308 chickens were randomly divided into 5 experiments and 4 treatment groups (8 replicates in each group of experiments). Guide cannula was surgically implanted into the lateral ventricle of chickens. In Experiment 1, birds received LPS (5, 10, and 20 ng) intracerebroventricularly (ICV). In Experiment 2, chickens were intraperitoneally (i.p.) injected with Indomethacin (5&nbsp;mg/kg) prior to LPS injection (20 ng; ICV). In Experiment 3, birds were i.p. injected with Aspirin (50 mg/kg) followed by LPS injection (20 ng; ICV). In Experiment 4, chickens were given LPS (20 ng; ICV) after Piroxicam injection (10 mg/kg; i.p.). In Experiment 5, chickens were injected with Celecoxib (10 mg/kg; i.p.) prior to LPS injection (20 ng; ICV). Cumulative feed intake was determined until 8 h post-injection. According to the results, LPS significantly decreased feed intake at 4 and 8 h post injection in birds (P &le; 0.05). Furthermore, LPS-induced hypophagia was attenuated by pre-injection with Indomethacin, Aspirin, and Celecoxib (P&nbsp;&le; 0.05). However, Piroxicam had no effect on LPS-induced hypophagia (P &ge; 0.05). These results suggest that presumably COX-2 mediates LPS-induced hypophagia in broilers.

Renal side effects of NSAIDs: role of COX-1 and COX-2

1998 ◽  
pp. 87-98 ◽  
Author(s):  
J. C. Frölich ◽  
D. O. Stichtenoth
Keyword(s):  
Side Effects ◽  
Cox 2 ◽  
Cox 1

Regulation of prostaglandin biosynthesis in vivo by glutathione

1998 ◽  
Vol 274 (2) ◽  
pp. R294-R302 ◽  
Author(s):  
Alon Margalit ◽  
Scott D. Hauser ◽  
Ben S. Zweifel ◽  
Melissa A. Anderson ◽  
Peter C. Isakson
Keyword(s):  
Reduced Glutathione ◽  
Intraperitoneal Administration ◽  
Peritoneal Macrophages ◽  
Urate Crystal ◽  
Cox 2 ◽  
Cox 1 ◽  
Urate Crystals

Intraperitoneal administration of urate crystals to mice reduced subsequent macrophage conversion of arachidonic acid (AA) to prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid for up to 6 h. In contrast, levels of 12-hydroxyheptadecatrienoic acid (12-HHT) were markedly elevated. This metabolic profile was previously observed in vitro when recombinant cyclooxygenase (COX) enzymes were incubated with reduced glutathione (GSH). Analysis of peritoneal GSH levels revealed a fivefold elevation after urate crystal administration. The GSH synthesis inhibitorl-buthionine-[ S, R]-sulfoximine partially reversed the urate crystal effect on both GSH elevation and PG synthesis. Moreover, addition of exogenous GSH to isolated peritoneal macrophages shifted AA metabolism from PGs to 12-HHT. Urate crystal administration reduced COX-1, but induced COX-2 expression in peritoneal cells. The reduction of COX-1 may contribute to the attenuation of PG synthesis after 1 and 2 h, but PG synthesis remained inhibited up to 6 h, when COX-2 levels were high. Overall, our results indicate that elevated GSH levels inhibit PG production in this model and provide in vivo evidence for the role of GSH in the regulation of PG biosynthesis.

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