scholarly journals Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis

2009 ◽  
Vol 425 (2) ◽  
pp. 361-371 ◽  
Author(s):  
Daisuke Kamei ◽  
Makoto Murakami ◽  
Yuka Sasaki ◽  
Yoshihito Nakatani ◽  
Masataka Majima ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumour Growth ◽  
Matrix Metalloproteinase 2 ◽  
Prostaglandin E ◽  
Wild Type ◽  
Prostaglandin E Synthase ◽  
Lung Carcinoma Cells ◽  
Microsomal Prostaglandin E Synthase

mPGES-1 (microsomal prostaglandin E synthase-1) is a stimulus-inducible enzyme that functions downstream of COX (cyclo-oxygenase)-2 in the PGE2 (prostaglandin E2)-biosynthesis pathway. Although COX-2-derived PGE2 is known to play a role in the development of various tumours, the involvement of mPGES-1 in carcinogenesis has not yet been fully understood. In the present study, we used LLC (Lewis lung carcinoma) cells with mPGES-1 knockdown or overexpression, as well as mPGES-1-deficient mice to examine the roles of cancer cell- and host-associated mPGES-1 in the processes of tumorigenesis in vitro and in vivo. We found that siRNA (small interfering RNA) silencing of mPGES-1 in LLC cells decreased PGE2 synthesis markedly, accompanied by reduced cell proliferation, attenuated Matrigel™ invasiveness and increased extracellular matrix adhesion. Conversely, mPGES-1-overexpressing LLC cells showed increased proliferating and invasive capacities. When implanted subcutaneously into wild-type mice, mPGES-1-silenced cells formed smaller xenograft tumours than did control cells. Furthermore, LLC tumours grafted subcutaneously into mPGES-1-knockout mice grew more slowly than did those grafted into littermate wild-type mice, with concomitant decreases in the density of microvascular networks, the expression of pro-angiogenic vascular endothelial growth factor, and the activity of matrix metalloproteinase-2. Lung metastasis of intravenously injected LLC cells was also significantly less obvious in mPGES-1-null mice than in wild-type mice. Thus our present approaches provide unequivocal evidence for critical roles of the mPGES-1-dependent PGE2 biosynthetic pathway in both cancer cells and host microenvironments in tumour growth and metastasis.

Prostaglandin E Synthase Is Upregulated By Gas6 during Cancer-Induced Venous Thromboembolism

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 111-111
Author(s):  
Meghedi N Aghourian ◽  
Catherine A Lemarie ◽  
Francois-Rene Bertin ◽  
Mark D Blostein
Keyword(s):  
Endothelial Cells ◽  
Venous Thromboembolism ◽  
Microarray Analysis ◽  
Conflicts Of Interest ◽  
Prostaglandin E ◽  
Wild Type ◽  
Prostaglandin E Synthase ◽  
Murine Lung

Abstract Venous thromboembolism (VTE) is the most common morbid complication related to cancer and its treatments. Although malignancies are characterized by a hypercoagulable state leading to VTE, the pathophysiology of this state has not been well studied. Growth arrest specific 6 (Gas6) is a protein that has pro-coagulant properties. Gas6 deficient mice develop smaller venous thrombi as compared to wild type mice, and express less tissue factor in the endothelium when challenged with thrombotic stimuli. We hypothesize that Gas6 may be involved in cancer-induced venous thrombosis. In order to test this hypothesis, venous thrombi were induced in wild type (WT) and Gas6 null (-/-) mice injected with M27 murine lung cancer cell lines. Thrombus size was measured using ultrasonography, thrombus weight and histology. We observed that WT mice with cancer developed larger thrombi than their healthy counterparts (p<0.05). However, these larger thrombi induced by cancer were not seen in Gas6-/- mice, suggesting that Gas6 has a pathophysiologic role in promoting malignancy associated VTE. Whole genome microarray analysis was then used to identify differential gene expression in WT and Gas6-/- endothelial cells co-cultured with M27 murine lung carcinoma cells. Microarray analysis revealed that prostaglandin E synthase (PTGES) was increased in WT endothelial cells but not in Gas6-/- cells co-cultured with M27. These results were confirmed using real-time PCR and immunofluorescence staining (p<0.05). In WT endothelial cells, PTGES expression was regulated through ERK1/2 phosphorylation. We also show that co-culture of WT endothelial cells with M27 augments the secretion of PGE2, the enzymatic product of PTGES. PGE2 activates platelets in vitro after binding to its receptor, EP3. In vivo, EP3 receptor antagonism reversed the effect of cancer-induced thrombosis in WT mice. These results show that Gas6, through upregulation of PGE2, contributes to cancer-induced VTE. Disclosures No relevant conflicts of interest to declare.

scholarly journals Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells

2009 ◽  
Vol 106 (44) ◽  
pp. 18757-18762 ◽  
Author(s):  
H. Hanaka ◽  
S.-C. Pawelzik ◽  
J. I. Johnsen ◽  
M. Rakonjac ◽  
K. Terawaki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
Prostaglandin E ◽  
Prostaglandin E Synthase ◽  
Microsomal Prostaglandin E Synthase

scholarly journals Effects of 1,25-Dihydroxy Vitamin D3 on Endometriosis

2016 ◽  
Vol 101 (6) ◽  
pp. 2371-2379 ◽  
Author(s):  
Mariko Miyashita ◽  
Kaori Koga ◽  
Gentaro Izumi ◽  
Fusako Sue ◽  
Tomoko Makabe ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Vitamin D3 ◽  
Serum Levels ◽  
Cell Counting ◽  
Prostaglandin E ◽  
Viable Cell Number ◽  
Prostaglandin E Synthase ◽  
1,25 Dihydroxy Vitamin D3 ◽  
Microsomal Prostaglandin E Synthase

Abstract Context: Endometriosis is an estrogen-dependent, chronic inflammatory disease. Recent studies have shown that vitamin D (VD) is an effective modulator of the immune system and plays an important role in controlling many inflammatory diseases. Objective: The objective of the study was to clarify the in vitro effects of 1,25-dihydroxy vitamin D3 (1,25[OH]2D3) on human endometriotic stromal cells (ESCs) and to determine the serum levels of VD in endometriosis patients. Design, Patients, and Main Outcome Measures: ESCs were isolated from ovarian endometrioma and cultured with 1,25(OH)2D3. Gene expression of IL-8, cyclooxygenase-2, microsomal prostaglandin E synthase-1, microsomal prostaglandin E synthase-2, cytosolic prostaglandin E synthase, 15-hydroxyprostaglandin dehydrogenase, matrix metalloproteinase (MMP)-2, and MMP-9 was examined using quantitative RT-PCR. The production of IL-8 and prostaglandin E2 was measured using an ELISA and an enzyme immunoassay. Viable cell number was assessed using a cell-counting assay, and DNA synthesis was assessed using the bromodeoxyuridine incorporation assay. Apoptosis was assessed using flow cytometry. The expression of inhibitory-κBα protein was detected using Western blotting. The serum levels of 25-hydroxyvitamin D3 and 1,25(OH)2D3 were measured by a RIA. Results: In vitro studies showed that 1,25(OH)2D3 significantly reduced IL-1β- or TNF-α-induced inflammatory responses, such as IL-8 expression and prostaglandin activity. 1,25(OH)2D3 also reduced viable ESC numbers and DNA synthesis but did not affect apoptosis. MMP-2 and MMP-9 expressions were reduced by 1,25(OH)2D3. 1,25(OH)2D3 inhibited nuclear factor-κB activation. The serum 25-hydroxyvitamin D3 levels were significantly lower in women with severe endometriosis than in the controls and women with mild endometriosis. Serum 1,25(OH)2D3 levels were not different between groups. Conclusions: VD modulates inflammation and proliferation in endometriotic cells, and a lower VD status is associated with endometriosis. Taken together, VD supplementation could be a novel therapeutic strategy for managing endometriosis.

scholarly journals 15-deoxy-Δ12,14-prostaglandin J2inhibits the expression of microsomal prostaglandin E synthase type 2 in colon cancer cells

2006 ◽  
Vol 47 (5) ◽  
pp. 1071-1080 ◽  
Author(s):  
Oliver Schröder ◽  
Yulyana Yudina ◽  
Alan Sabirsh ◽  
Nadine Zahn ◽  
Jesper Z. Haeggström ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Prostaglandin E ◽  
Colon Cancer Cells ◽  
Prostaglandin E Synthase ◽  
Microsomal Prostaglandin E Synthase

Sulforaphane, a Chemopreventive Compound, Inhibits Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Expression in Human HT-29 Colon Cancer Cells

2018 ◽  
Vol 206 (1-2) ◽  
pp. 46-53 ◽  
Author(s):  
Maryam Sadat Tafakh ◽  
Massoud Saidijam ◽  
Tayebeh Ranjbarnejad ◽  
Sara Malih ◽  
Solmaz Mirzamohammadi ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Caspase 3 ◽  
Mrna Level ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Prostaglandin E Synthase ◽  
Cox 2 ◽  
Ht 29 ◽  
Microsomal Prostaglandin E Synthase

Background: A high expression of prostaglandin E2 (PGE2) is found in colorectal cancer. Therefore, blocking of PGE2 generation has been identified as a promising approach for anticancer therapy. Sulforaphane (SFN), an isothiocyanate derived from glucosinolate, is used as the antioxidant and anticancer agents. Methods: HT-29 cells were treated with various concentrations of SFN and compared to untreated cells for the expression of microsomal prostaglandin E synthase-1 (mPGES-1), cyclooxygenase 2 (COX-2), hypoxia-inducible factor-1 (HIF-1), C-X-C chemokine receptor type 4 (CXCR4), vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP)-2 and MMP-9 at the mRNA level. The PGE2 level was measured by ELISA assay. Apoptosis was evaluated by the proportion of sub-G1 cells. The activity of caspase-3 was determined using an enzymatic assay. HT-29 cell migration was assessed using a scratch test. Results: SFN preconditioning decreased the expression of COX-2, mPGES-1, HIF-1, VEGF, CXCR4, MMP-2, and MMP-9. An apoptotic effect of SFN was preceded by the activation of caspase-3 as well as accumulation of cells in the sub-G1 phase of the cell cycle. SFN decreased PGE2 generation and inhibited the in vitro motility/wound-healing activity of HT-29 cells. Conclusions: SFN anticancer effects are associated with antiproliferative, antiangiogenic, and antimetastatic activities arising from the downregulation of the COX-2/ mPGES-1 axis.

Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/β-catenin pathway

2017 ◽  
Vol 474 (22) ◽  
pp. 3733-3746 ◽  
Author(s):  
Fatima Lahdaoui ◽  
Mathieu Messager ◽  
Audrey Vincent ◽  
Flora Hec ◽  
Anne Gandon ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Gastrointestinal Cancer ◽  
Tumour Growth ◽  
Cancer Cell Line ◽  
Migration And Invasion ◽  
Down Regulation

Secreted mucins are large O-glycosylated proteins that participate in the protection/defence of underlying mucosae in normal adults. Alteration of their expression is a hallmark of numerous epithelial cancers and has often been correlated to bad prognosis of the tumour. The secreted mucin MUC5B is overexpressed in certain subtypes of gastric and intestinal cancers, but the consequences of this altered expression on the cancer cell behaviour are not known. To investigate the role of MUC5B in carcinogenesis, its expression was knocked-down in the human gastric cancer cell line KATO-III and in the colonic cancer cell line LS174T by using transient and stable approaches. Consequences of MUC5B knocking-down on cancer cells were studied with respect to in vitro proliferation, migration and invasion, and in vivo on tumour growth using a mouse subcutaneous xenograft model. Western blotting, luciferase assay and qRT–PCR were used to identify proteins and signalling pathways involved. In vitro MUC5B down-regulation leads to a decrease in proliferation, migration and invasion properties in both cell lines. Molecular mechanisms involved the alteration of β-catenin expression, localization and activity and decreased expression of several of its target genes. In vivo xenografts of MUC5B-deficient cells induced a decrease in tumour growth when compared with MUC5B-expressing Mock cells. Altogether, the present study shows that down-regulation of MUC5B profoundly alters proliferation, migration and invasion of human gastrointestinal cancer cells and that these alterations may be, in part, mediated by the Wnt/β-catenin pathway emphasizing the potential of MUC5B as an actor of gastrointestinal carcinogenesis.

scholarly journals Microsomal prostaglandin E synthase-2 is not essential for in vivo prostaglandin E2 biosynthesis

2009 ◽  
Vol 88 (3-4) ◽  
pp. 73-81 ◽  
Author(s):  
Leigh A. Jania ◽  
Subhashini Chandrasekharan ◽  
Michael G. Backlund ◽  
Nicholas A. Foley ◽  
John Snouwaert ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Prostaglandin E ◽  
Prostaglandin E Synthase ◽  
Microsomal Prostaglandin E Synthase

IL-1β and LPS induce anorexia by distinct mechanisms differentially dependent on microsomal prostaglandin E synthase-1

2007 ◽  
Vol 292 (1) ◽  
pp. R258-R267 ◽  
Author(s):  
Louise Elander ◽  
Linda Engström ◽  
Martin Hallbeck ◽  
Anders Blomqvist
Keyword(s):  
Body Weight ◽  
Body Weight Loss ◽  
Automated System ◽  
Prostaglandin E ◽  
Wild Type ◽  
Experimental Conditions ◽  
Prostaglandin E Synthase ◽  
Knock Out ◽  
Knock Out Mice ◽  
Microsomal Prostaglandin E Synthase

Recent work demonstrated that the febrile response to peripheral immune stimulation with proinflammatory cytokine IL-1β or bacterial wall lipopolysaccharide (LPS) is mediated by induced synthesis of prostaglandin E2 by the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). The present study examined whether a similar mechanism might also mediate the anorexia induced by these inflammatory agents. Transgenic mice with a deletion of the Ptges gene, which encodes mPGES-1, and wild-type controls were injected intraperitoneally with IL-1β, LPS, or saline. Mice were free fed, and food intake was continuously monitored with an automated system for 12 h. Body weight was recorded every 24 h for 4 days. The IL-1β induced anorexia in wild-type but not knock-out mice, and so it was almost completely dependent on mPGES-1. In contrast, LPS induced anorexia of the same magnitude in both phenotypes, and hence it was independent of mPGES-1. However, when the mice were prestarved for 22 h, LPS induced anorexia and concomitant body weight loss in the knock-out animals that was attenuated compared with the wild-type controls. These data suggest that IL-1β and LPS induce anorexia by distinct immune-to-brain signaling pathways and that the anorexia induced by LPS is mediated by a mechanism different from the fever induced by LPS. However, nutritional state and/or motivational factors also seem to influence the pathways for immune signaling to the brain. Furthermore, both IL-1β and LPS caused reduced meal size but not meal frequency, suggesting that both agents exerted an anhedonic effect during these experimental conditions.

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