Epigenetic modification of the COX-2/PGE2 pathway modulates macrophage phenotype and cell-targeted manipulation improves diabetic tissue repair
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PROVIDER: PRJNA646694 | ENA |
REPOSITORIES: ENA
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Project description:Chromosome 17p deletions are one of the most frequent chromosomal alterations in human cancers and also lymphoma. Although it has been assumed to be equal to p53 loss for a long time, there are emerging evidence suggesting that there would be additional p53–independent mechanisms. Our previous work identified ALOX15B, an arachidonate lipoxygenase, as a 17p tumor suppressor in lymphoma. Interestingly, five of the six ALOX genes locate on this region and frequently co-deleted with TP53. Among them, ALOX15B, ALOX12B and ALOXE3 are adjacent to one another and proximal to the centromere relative to TP53, while ALOX12 and ALOX15 are distal to the centromere relative to TP53. Herein, we show that each of the five 17p ALOX genes repress Myc-driven lymphomagenesis in mice. Mechanistically, deficiency of the ALOX arachidonate metabolism pathway activates the paralleling COX-PGE2 pathway, resulting in increasing PTGS2 expression and PGE2 level. PGE2 prevents apoptosis of pre-B cells and Ptgs2 knockdown extends the latency of Myc;shAlox15b lymphoma in vivo. Further, shAlox15b lymphoma cells are more sensitive to COX-2 inhibitor celecoxib than control lymphoma cells. Importantly, the ALOX-COX metabolism unbalance is also observed in human cancers with del(17p). Taken together, our studies reveal the tumor suppression functions of all of the five ALOX genes on chromosome 17p in lymphoma and an unprecedented arachidonate metabolism unbalance between the ALOX and COX pathways underlying human cancers with 17p deletions.
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Project description:Prostaglandin E2 (PGE2) is overexpressed in many tumors and plays an important role in suppressing T-cell function. In this study, we investigated the effect of PGE2 in human T-cells. Importantly, PGE2 caused profound transcriptomic changes both in unstimulated and exhausted T-cells with many genes and pathways altered including T-cell lipid metabolism. Our study suggests that PGE2-induced metabolic reprogramming is detrimental to dysfunctional T-cells and TIL, and its manipulation could be used to dampen the immunosuppressive effects of PGE2.
2024-03-08 | GSE227316 | GEO
Project description:To comprehensively understand how dendritic cells (DCs) are reprogrammed by lung fibroblasts- and their derived COX-2/PGE2, we employed lung fibroblasts isolated from WT or Ptgs2-/- mice, and collect their conditioned medium (CM) to stimulate the ex vivo cultured bone marrow (BM)-derived DCs (BM-DCs), with the PGE2 treatment as a control. After the treatment, BM-DCs were harvested for RNA extraction and the transcriptional profiles were analyzed by RNA sequencing (RNA-seq).
2022-07-19 | E-MTAB-11873 | biostudies-arrayexpress
Project description:Prostaglandin E2 (PGE2) is involved in several inflammatory conditions including periodontitis. The aim of this study was to investigate the global gene expression profile of tumor necrosis factor alpha (TNFalpha) stimulated human gingival fibroblasts, focusing on signal pathways related to PGE2 production and the new PGE2-synthesizing enzymes, prostaglandin E synthases (PGES). The expression of microsomal prostaglandin E synthase-1 (mPGES-1) as well as the upstream cyclooxygenase-2 (COX-2) was up-regulated by TNFalpha, accompanied by increased PGE2 production. In contrast, the expression of microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFalpha. Using microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, we identified differentially expressed genes in response to TNFalpha treatment. Enrichment analysis of microarray data identified two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-kappaB (NF-kappaB). We used specific inhibitors and phosphorylation analysis to confirm their role in PGE2 regulation. Both JNK and NF-kappaB inhibitors reduced the TNFalpha-stimulated up-regulation of mPGES-1 and COX-2 as well as subsequent PGE2 production. The novel finding that TNFalpha-stimulated mPGES-1 is regulated by JNK suggests this kinase as a potential future target for treatment strategies in inflammatory disorders, including periodontitis. Keywords: Time course, gene expression, factorial design.
2008-12-11 | GSE13903 | GEO
Project description:We compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1β induced A549 lung cancer cells using mass spectrometry. Inhibition of mPGES-1 decreased PGE2 production and increased PGF2α and thromboxane B2 (TXB2) formation, while inhibition of COX-2 decreased the production of all three prostanoids. Our proteomics results revealed that CIII downregulated multiple canonical pathways including eIF2, eIF4/P70S6K, and mTOR signaling, compared to NS-398 that activated these pathways.
2019-05-20 | PXD013490 | Pride
Project description:Prostaglandin E2 (PGE2) is involved in several inflammatory conditions including periodontitis. The aim of this study was to investigate the global gene expression profile of tumor necrosis factor alpha (TNFalpha) stimulated human gingival fibroblasts, focusing on signal pathways related to PGE2 production and the new PGE2-synthesizing enzymes, prostaglandin E synthases (PGES). The expression of microsomal prostaglandin E synthase-1 (mPGES-1) as well as the upstream cyclooxygenase-2 (COX-2) was up-regulated by TNFalpha, accompanied by increased PGE2 production. In contrast, the expression of microsomal prostaglandin E synthase-2 (mPGES-2) and cytosolic prostaglandin E synthase (cPGES) was unaffected by TNFalpha. Using microarray analysis in a time-course factorial design including time points 1, 3 and 6 h, we identified differentially expressed genes in response to TNFalpha treatment. Enrichment analysis of microarray data identified two positively regulated signal transduction pathways: c-Jun N-terminal kinase (JNK) and Nuclear Factor-kappaB (NF-kappaB). We used specific inhibitors and phosphorylation analysis to confirm their role in PGE2 regulation. Both JNK and NF-kappaB inhibitors reduced the TNFalpha-stimulated up-regulation of mPGES-1 and COX-2 as well as subsequent PGE2 production. The novel finding that TNFalpha-stimulated mPGES-1 is regulated by JNK suggests this kinase as a potential future target for treatment strategies in inflammatory disorders, including periodontitis. Keywords: Time course, gene expression, factorial design. Three human gingival fibroblast cell lines were established from gingival biopsies obtained from 3 healthy patients, 3 to 12 years of age, with no clinical signs of periodontal disease. Cells were incubated with or without TNF-alpha (20 ng/ml) for 1, 3 or 6h. After incubation for 1, 3 or 6 h in the two conditions, the cells were immediately frozen in liquid nitrogen and then stored at -70°C for subsequent isolation of total RNA. The experimental design of the microarray study was set up as a time-course factorial design, to best observe the TNF-alpha induced gene expression changes over time. C++ program (G.F. Glonek, P.J. Solomon, Factorial and time course designs for cDNA microarray experiments, Biostatistics 5 (2004) 89-111) was used to determine the exact layout of the design in order to estimate the interaction effect between treatment and time, i.e. genes that are differentially expressed over time, with optimal statistical efficiency. Cyanine 5 and cyanine 3 were used for labeling. For each cell line 12 hybridizations were performed in a time-course factorial design. In total, 36 hybridizations were performed.
2008-12-10 | E-GEOD-13903 | biostudies-arrayexpress
Project description:We combined phosphoproteomics and phosphoflow cytometry with specific stimulation of the four PGE2 receptors to obtain a global overview of PGE2-regulated signaling pathways and networks in T cells. The study revealed phosphoproteomes regulated uniquely by each receptor and crosstalk between receptors. Previously unknown PGE2-regulated phosphosites were identified, including biologically significant sites.
2021-08-22 | PXD014503 | Pride
Project description:To further understand the physiological role of cyclooxygenase (COX), the critical enzyme involved in the production of eicosanoids from arachidonic acid, we performed microarray analysis of gene expression in the cerebral cortex and hippocampus of mice deficient in COX-1 (COX-1-/-) or COX-2 (COX-2-/-). Expression of lipid (ATP citrate lyase, acetyl-CoA acetyltransferase, hydroxyacyl-CoA dehydrogenase) and homocysteine (methionine adenosyltransferase, S-adenosylhomocysteine hydrolase) metabolism genes was increased in the cerebral cortex of COX-2 -/- mice. Further, expression of GABAergic neurotransmission genes (GABA transporter 3, GABA-A receptor subunit ?1) was altered in the cerebral cortex and hippocampus of COX-2 -/- mice. A COX isoform specific effect was observed in the expression of Janus Kinase (JAK) 1 and 2. COX-1 -/- mice exhibited an increase in JAK1 expression while COX-2 -/- mice exhibited a decrease in JAK2 expression, an observation consistent with a previously demonstrated COX isoform specific effect on the expression of NF-kB. In summary, this study demonstrates the wide ranging effects of genetic deletion of COX isoforms in the mouse brain and suggests that inhibition of COX activity may alter the profile of gene expression in specific areas of the brain. We used nylon cDNA microarrays to detail the global programme of gene expression in the Cerebral Cortex and Hippocampus of COX-1 and COX-2 null (knockout) mice Keywords: brain, cerebral cortex, hippocampus, COX-1 WT, COX-1 KO, COX-2 WT, COX-2 KO and COX-2 heterozygous
2007-02-05 | GSE5342 | GEO
Project description:While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well-established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small molecule antagonists of single EP receptors, the COX-2 inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared to single EP antagonists. CD8+ T cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased TME lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared to celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small molecule dual EP2/EP4 antagonist.
2023-08-21 | GSE229806 | GEO