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Aspects of Prostaglandin Glycerol Ester Biology.
Kingsley PJ, Rouzer CA, Morgan AJ, Patel S, Marnett LJ
(2019) Adv Exp Med Biol 1161: 77-88
MeSH Terms: Animals, Arachidonic Acids, Cyclooxygenase 2, Endocannabinoids, Glycerides, Glyceryl Ethers, Prostaglandins
Show Abstract · Added March 12, 2020
The Cyclooxygenase enzymes (COX-1 and COX-2) incorporate 2 molecules of O into arachidonic acid (AA), resulting in an array of bioactive prostaglandins. However, much work has been done showing that COX-2 will perform this reaction on several different AA-containing molecules, most importantly, the endocannabinoid 2-arachidonoylglycerol (2-AG). The products of 2-AG oxygenation, prostaglandin glycerol esters (PG-Gs), are analogous to canonical prostaglandins. This chapter reviews the literature detailing the production, metabolism, and bioactivity of these compounds, as well as their detection in intact animals.
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IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.
Chopra S, Giovanelli P, Alvarado-Vazquez PA, Alonso S, Song M, Sandoval TA, Chae CS, Tan C, Fonseca MM, Gutierrez S, Jimenez L, Subbaramaiah K, Iwawaki T, Kingsley PJ, Marnett LJ, Kossenkov AV, Crespo MS, Dannenberg AJ, Glimcher LH, Romero-Sandoval EA, Cubillos-Ruiz JR
(2019) Science 365:
MeSH Terms: Animals, Cells, Cultured, Cyclooxygenase 2, Dinoprostone, Endoribonucleases, Humans, Leukocytes, Mice, Mice, Inbred C57BL, Myeloid Cells, Pain, Postoperative, Promoter Regions, Genetic, Prostaglandin-E Synthases, Protein-Serine-Threonine Kinases, Signal Transduction, Unfolded Protein Response, Visceral Pain, X-Box Binding Protein 1
Show Abstract · Added March 12, 2020
Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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18 MeSH Terms
Renal Medullary Interstitial COX-2 (Cyclooxygenase-2) Is Essential in Preventing Salt-Sensitive Hypertension and Maintaining Renal Inner Medulla/Papilla Structural Integrity.
Zhang MZ, Wang S, Wang Y, Zhang Y, Ming Hao C, Harris RC
(2018) Hypertension 72: 1172-1179
MeSH Terms: Animals, Apoptosis, Aquaporin 2, Blood Pressure, Cyclooxygenase 2, Epithelial Sodium Channels, Hypertension, Kidney Medulla, Mice, Mice, Transgenic
Show Abstract · Added November 8, 2018
COX (cyclooxygenase)-derived prostaglandins regulate renal hemodynamics and salt and water homeostasis. Inhibition of COX activity causes blood pressure elevation. In addition, chronic analgesic abuse can induce renal injury, including papillary necrosis. COX-2 is highly expressed in the kidney papilla in renal medullary interstitial cells (RMICs). However, its role in blood pressure and papillary integrity in vivo has not been definitively studied. In mice with selective, inducible RMIC COX-2 deletion, a high-salt diet led to an increase in blood pressure that peaked at 4 to 5 weeks and was associated with increased papillary expression of AQP2 (aquaporin 2) and ENac (epithelial sodium channel) and decreased expression of cystic fibrosis transmembrane conductance regulator. With continued high-salt feeding, the mice with RMIC COX-2 deletion had progressive decreases in blood pressure from its peak. After return to a normal-salt diet for 3 weeks, blood pressure remained low and was associated with a persistent urinary concentrating defect. Within 2 weeks of institution of a high-salt diet, increased apoptotic RMICs and collecting duct cells could be detected in papillae with RMIC deletion of COX-2, and by 9 weeks of high salt, there was a striking loss of the papillae. Therefore, RMIC COX-2 expression plays a crucial role in renal handling water and sodium homeostasis, preventing salt-sensitive hypertension and maintaining structural integrity of papilla.
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10 MeSH Terms
Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain.
Morgan AJ, Kingsley PJ, Mitchener MM, Altemus M, Patrick TA, Gaulden AD, Marnett LJ, Patel S
(2018) ACS Chem Neurosci 9: 1552-1559
MeSH Terms: Animals, Arachidonic Acids, Brain, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Endocannabinoids, Esters, Female, Glycerides, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Mice, Transgenic, Monoacylglycerol Lipases, Neurons, Oxidation-Reduction, Prostaglandins
Show Abstract · Added October 8, 2018
Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.
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Differential cyclooxygenase expression levels and survival associations in type I and type II ovarian tumors.
Beeghly-Fadiel A, Wilson AJ, Keene S, El Ramahi M, Xu S, Marnett LJ, Fadare O, Crispens MA, Khabele D
(2018) J Ovarian Res 11: 17
MeSH Terms: Aged, Biomarkers, Tumor, Cyclooxygenase 1, Cyclooxygenase 2, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Middle Aged, Neoplasm Grading, Neoplasm Staging, Ovarian Neoplasms, Prognosis, Proportional Hazards Models, Prostaglandin-Endoperoxide Synthases
Show Abstract · Added March 21, 2018
BACKGROUND - High cyclooxygenase (COX)-2 expression in ovarian tumors has been associated with poor prognosis, but the role of COX-1 expression and its relation to survival is less clear. Here, we evaluated COX expression and associations with survival outcomes between type I (clear cell, mucinous, low grade endometrioid and low grade serous) and type II (high grade serous and high grade endometrioid) ovarian tumors.
METHODS - We developed and validated a new COX-1 antibody, and conducted immunohistochemical (IHC) staining for COX-1 and COX-2 on a tissue microarray (TMA) of 190 primary ovarian tumors. In addition to standard IHC scoring and H-scores to combine the percentage of positive cells and staining intensity, we also measured COX-1 and COX-2 mRNA expression by QPCR. High expression was defined as greater than or equal to median values. Clinical characteristics and disease outcomes were ascertained from medical records. Associations with disease-free survival (DFS) and overall survival (OS) were quantified by hazard ratios (HRs) and confidence intervals (CIs) from proportional hazards regression.
RESULTS - Type I tumors had high COX-2 expression, while type II tumors had high COX-1 expression. In multivariable adjusted regression models, higher COX-1 mRNA expression was associated with shorter DFS (HR: 6.37, 95% CI: 1.84-22.01) and OS (HR: 2.26, 95% CI: 1.04-4.91), while higher H-scores for COX-2 expression were associated with shorter DFS (HR: 1.92, 95% CI: 1.06-3.49). Stratified analysis indicated that COX-2 was significantly associated with DFS among cases with Type II tumors (HR: 1.93, 95% CI: 1.06-3.53).
CONCLUSIONS - These findings suggest that ovarian tumor type contributes to differences in COX expression levels and associations with survival.
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Prospective study of urinary prostaglandin E2 metabolite and pancreatic cancer risk.
Cui Y, Shu XO, Li HL, Yang G, Wen W, Gao YT, Cai Q, Rothman N, Yin HY, Lan Q, Xiang YB, Zheng W
(2017) Int J Cancer 141: 2423-2429
MeSH Terms: Adult, Aged, Body Mass Index, Case-Control Studies, China, Chromatography, Liquid, Cyclooxygenase 2, Female, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Pancreatic Neoplasms, Prospective Studies, Prostaglandins, Tandem Mass Spectrometry
Show Abstract · Added April 3, 2018
The cyclooxygenase 2 (COX-2) pathway is upregulated in many pancreatic cancer cells, and it is believed that carcinogenetic effects of COX-2 upregulation are largely through prostaglandin E2 (PGE2) overproduction. We tested this hypothesis by evaluating the association between urinary PGE2 metabolites (PGE-M), a biomarker of in vivo PGE2 overproduction, and pancreatic cancer risk. We conducted a case-control study with 722 subjects (239 cases and 483 controls) nested within two prospective cohort studies, the Shanghai Women's Health Study (SWHS) and Shanghai Men's Health Study (SMHS). Pre-diagnosis urine samples were measured for PGE-M using a liquid chromatography/tandem mass spectrometric method. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (95%CI), with adjustment for potential confounders. Compared to those with the lowest urine level of PGE-M (the first quartile), individuals with higher urine levels of PGE-M had an increased risk of developing pancreatic cancer, with adjusted ORs (95%CI) of 1.63 (0.98-2.73), 1.55 (0.90-2.69) and 1.94 (1.07-3.51), for the second to the fourth quartile groups, respectively (p for trend = 0.054). This dose-response positive association was more evident among those who had BMI <25 kg/m than overweight individuals (p for interaction = 0.058). After excluding cases diagnosed in the first year of follow-up and their matched controls, this positive association persisted (p for trend = 0.037) and the interaction became statistically significant (p for interaction = 0.017). Our study adds additional evidence that the COX-2 pathway is involved in pancreatic carcinogenesis and suggests that urinary PGE-M may serve as a biomarker for predicting pancreatic cancer risk.
© 2017 UICC.
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Prostaglandin E glyceryl ester is an endogenous agonist of the nucleotide receptor P2Y.
Brüser A, Zimmermann A, Crews BC, Sliwoski G, Meiler J, König GM, Kostenis E, Lede V, Marnett LJ, Schöneberg T
(2017) Sci Rep 7: 2380
MeSH Terms: Animals, Binding Sites, Cell Line, Tumor, Cyclooxygenase 2, Dinoprostone, HEK293 Cells, High-Throughput Nucleotide Sequencing, High-Throughput Screening Assays, Humans, Kinetics, Ligands, Mice, Molecular Docking Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Purinergic Agonists, RAW 264.7 Cells, Receptors, Purinergic P2, Substrate Specificity, Thermodynamics, Transcriptome
Show Abstract · Added March 17, 2018
Cyclooxygenase-2 catalyses the biosynthesis of prostaglandins from arachidonic acid but also the biosynthesis of prostaglandin glycerol esters (PG-Gs) from 2-arachidonoylglycerol. Previous studies identified PG-Gs as signalling molecules involved in inflammation. Thus, the glyceryl ester of prostaglandin E, PGE-G, mobilizes Ca and activates protein kinase C and ERK, suggesting the involvement of a G protein-coupled receptor (GPCR). To identify the endogenous receptor for PGE-G, we performed a subtractive screening approach where mRNA from PGE-G response-positive and -negative cell lines was subjected to transcriptome-wide RNA sequencing analysis. We found several GPCRs that are only expressed in the PGE-G responder cell lines. Using a set of functional readouts in heterologous and endogenous expression systems, we identified the UDP receptor P2Y as the specific target of PGE-G. We show that PGE-G and UDP are both agonists at P2Y, but they activate the receptor with extremely different EC values of ~1 pM and ~50 nM, respectively. The identification of the PGE-G/P2Y pair uncovers the signalling mode of PG-Gs as previously under-appreciated products of cyclooxygenase-2.
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23 MeSH Terms
Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy.
Wang X, Yao B, Wang Y, Fan X, Wang S, Niu A, Yang H, Fogo A, Zhang MZ, Harris RC
(2017) Diabetes 66: 494-504
MeSH Terms: Albuminuria, Animals, Cells, Cultured, Cyclooxygenase 2, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Fibrosis, Immunoblotting, Immunohistochemistry, Kidney, Macrophages, Male, Mice, Mice, Knockout, NF-kappa B, Neutrophil Infiltration, Neutrophils, Nitric Oxide Synthase Type II, Real-Time Polymerase Chain Reaction, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, T-Lymphocytes
Show Abstract · Added April 26, 2017
Diabetic nephropathy (DN) is characterized by increased macrophage infiltration, and proinflammatory M1 macrophages contribute to development of DN. Previous studies by us and others have reported that macrophage cyclooxygenase-2 (COX-2) plays a role in polarization and maintenance of a macrophage tissue-reparative M2 phenotype. We examined the effects of macrophage COX-2 on development of DN in type 1 diabetes. Cultured macrophages with COX-2 deletion exhibited an M1 phenotype, as demonstrated by higher inducible nitric oxide synthase and nuclear factor-κB levels but lower interleukin-4 receptor-α levels. Compared with corresponding wild-type diabetic mice, mice with COX-2 deletion in hematopoietic cells (COX-2 knockout bone marrow transplantation) or macrophages (CD11b-Cre COX2) developed severe DN, as indicated by increased albuminuria, fibrosis, and renal infiltration of T cells, neutrophils, and macrophages. Although diabetic kidneys with macrophage COX-2 deletion had more macrophage infiltration, they had fewer renal M2 macrophages. Diabetic kidneys with macrophage COX-2 deletion also had increased endoplasmic reticulum stress and decreased number of podocytes. Similar results were found in diabetic mice with macrophage PGE receptor subtype 4 deletion. In summary, these studies have demonstrated an important but unexpected role for macrophage COX-2/prostaglandin E/PGE receptor subtype 4 signaling to lessen progression of diabetic kidney disease, unlike the pathogenic effects of increased COX-2 expression in intrinsic renal cells.
© 2017 by the American Diabetes Association.
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Fluorocoxib A enables targeted detection of cyclooxygenase-2 in laser-induced choroidal neovascularization.
Uddin MJ, Moore CE, Crews BC, Daniel CK, Ghebreselasie K, McIntyre JO, Marnett LJ, Jayagopal A
(2016) J Biomed Opt 21: 90503
MeSH Terms: Animals, Choroidal Neovascularization, Cyclooxygenase 2, Feasibility Studies, Image Processing, Computer-Assisted, Indoles, Mice, Optical Imaging, Rhodamines
Show Abstract · Added April 22, 2018
Ocular angiogenesis is a blinding complication of age-related macular degeneration and other retinal vascular diseases. Clinical imaging approaches to detect inflammation prior to the onset of neovascularization in these diseases may enable early detection and timely therapeutic intervention. We demonstrate the feasibility of a previously developed cyclooxygenase-2 (COX-2) targeted molecular imaging probe, fluorocoxib A, for imaging retinal inflammation in a mouse model of laser-induced choroidal neovascularization. This imaging probe exhibited focal accumulation within laser-induced neovascular lesions, with minimal detection in proximal healthy tissue. The selectivity of the probe for COX-2 was validated
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Antitumor Activity of Cytotoxic Cyclooxygenase-2 Inhibitors.
Uddin MJ, Crews BC, Xu S, Ghebreselasie K, Daniel CK, Kingsley PJ, Banerjee S, Marnett LJ
(2016) ACS Chem Biol 11: 3052-3060
MeSH Terms: Animals, Antineoplastic Agents, Cell Line, Tumor, Crystallography, X-Ray, Cyclooxygenase 2 Inhibitors, Humans, Kinetics, Mice, Mice, Nude
Show Abstract · Added April 14, 2017
Targeted delivery of chemotherapeutic agents to tumors has been explored as a means to increase the selectivity and potency of cytotoxicity. Most efforts in this area have exploited the molecular recognition of proteins highly expressed on the surface of cancer cells followed by internalization. A related approach that has received less attention is the targeting of intracellular proteins by ligands conjugated to anticancer drugs. An attractive target for this approach is the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in a range of malignant tumors. Herein, we describe the synthesis and evaluation of a series of chemotherapeutic agents targeted to COX-2 by conjugation to indomethacin. Detailed characterization of compound 12, a conjugate of indomethacin with podophyllotoxin, revealed highly potent and selective COX-2 inhibition in vitro and in intact cells. Kinetics and X-ray crystallographic studies demonstrated that compound 12 is a slow, tight-binding inhibitor that likely binds to COX-2's allosteric site with its indomethacin moiety in a conformation similar to that of indomethacin. Compound 12 exhibited cytotoxicity in cell culture similar to that of podophyllotoxin with no evidence of COX-2-dependent selectivity. However, in vivo, compound 12 accumulated selectively in and more effectively inhibited the growth of a COX-2-expressing xenograft compared to a xenograft that did not express COX-2. Compound 12, which we have named chemocoxib A, provides proof-of-concept for the in vivo targeting of chemotherapeutic agents to COX-2 but suggests that COX-2-dependent selectivity may not be evident in cell culture-based assays.
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9 MeSH Terms