Transcriptional profiing of cultured adherent and non-adherent monocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE161839 | GEO | 2020/12/08
REPOSITORIES: GEO
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Project description:2-deoxy-D-glucose (2DG) is a glucose analog that is established to inhibit glucose metabolism via glycolysis. It has long been recognized as a potential chemical mimetic of calorie restriction, and it also has been shown to have anti-viral effects in infected cells, against among others SARS-CoV-2. This study aimed to determine whether intermittent treatment of mice with 2DG could alter nutrient metabolism in vivo and whether this would produce a proteomic signature of altered glucose metabolism and other cellular pathways, with a view to explaining the anti-viral properties of 2DG. Parallel physiological studies of the heart aimed to relate any proteomic changes to the function and performance of the heart, including assessing whether there were any signs of detrimental effects of 2DG.
2022-05-20 | PXD027974 | Pride
Project description:Transcriptional profiing of cultured adherent and non-adherent monocytes
| PRJNA679607 | ENA
Project description:Spautin-1 as well as buformin showed preferential cytotoxicity under 2-deoxy-D-glucose (2DG)-stressed, but not tunicamycin-stressed conditions in HT-29 cells. By a microarray-based transcription analyses, we previously identified an unfolded protein response (UPR) expression signature, consisting of 246 probes up- or down-regulated in glucose starvation- and 2DG-stressed HT-29 and other cancer cell lines. Thus, we compared the effects of spautin-1 and buformin on the UPR transcriptional program. The two UPR inhibitors partly canceled 2DG-induced, but not TM-induced changes in UPR expression signature, indicating that spautin-1 can indeed suppress the UPR transcriptional program under 2DG-stressed conditions.
2022-07-07 | GSE189850 | GEO
Project description:Cancer cells display an altered metabolism with increased glycolysis and glucose uptake. Anti-cancer strategies targeting glycolysis through metabolic inhibitors have been considered. The glucose analog 2-deoxyglucose (2DG) is imported into cells and after phosphorylation becomes 2DG-6-phosphate, a toxic by-product that inhibits glycolysis. 2DG has other cellular effects and can induce resistance. Using yeast as a model, we performed an unbiased, mass-spectrometry-based approach to probe the cellular effects of 2DG on the proteome and study resistance mechanisms. We found that two 2DG-6-phosphate phosphatases, Dog1 and Dog2, were induced upon exposure to 2DG and participated in 2DG detoxication. 2DG induced Dog2 by activating several signaling pathways, such as the MAPK (the p38 ortholog Hog1)-based stress-responsive pathway, the unfolded protein response (UPR) triggered by 2DG-induced ER stress, and the MAPK (Slt2)-based cell wall integrity (CWI) pathway. Thus, 2DG-induced interference with cellular signaling rewired the expression of these endogenous phosphatases to promote 2DG resistance. Consequently, loss of the UPR or CWI pathways led to 2DG hypersensitivity. In contrast, DOG2 was transcriptionally repressed by glucose availability through the inhibition of the Snf1/AMPK pathway, and glucose-repression mutants were 2DG-resistant. The characterization and genome resequencing of spontaneous 2DG-resistant mutants revealed that DOG2 overexpression was a common strategy to achieve 2DG resistance. A human Dog2 homolog, HDHD1, also displays 2DG-6-phosphate phosphatase activity in vitro, and its overexpression conferred 2DG resistance in HeLa cells, suggesting potential interference with chemotherapies involving 2DG.
2019-09-09 | PXD014373 | Pride
Project description:Inhibiting the unfolded protein response (UPR) can be a therapeutic approach, especially for targeting the tumor microenvironment. We found that compound C (also known as dorsomorphin) prevented the UPR and exerted enhanced cytotoxicity during glucose deprivation. The UPR-inhibiting activity of compound C was not associated with either AMPK or BMP signaling inhibition. To induce the UPR, we treated HT1080 cells for 18 hours under ER stress conditions by adding 10 mM 2-Deoxy-D-glucose (2DG) to culture medium. UPR inhibitors (compound C, versipelostatin and phenformin) were added just before 2DG was added in medium. Total 8 samples were prepared for RNA extraction and hybridization on Affymetrix microarrays.
2012-10-11 | E-GEOD-32911 | biostudies-arrayexpress
Project description:The Warburg effect, consisting of increased glucose uptake and glycolysis, provides metabolic energy as well as cellular building blocks for tumor growth. Inhibition of the Warburg effect with 2-deoxyglucose (2DG) has been explored in clinical trials with limited efficacy. Blockage of glycolysis can induce autopahgy resulting in alternative energy generation through oxidative phosphorylation providing a potential bypass of the effects of inhibition of glycolysis. Here in we demonstrate that activation of AMPK, as a consequence of energetic stress, induces mitochondrial energy production potentially bypassing the effects of glycolysis inhibition. We thus combined blockage of glycolysis by 2DG with inhibition of the electron transfer complex I (ETC1) in the mitochondria with the clinically applicable antidiabetic drug metformin. The combination resulted in activation of AMPK and autopahgy that however rendered eventual depletion of ATP and cell death. Furthermore, combined inhibition of glycolysis and mitochondrial respiration inhibited tumor growth and markedly decreased metastatic capacity in vivo. In order to understand the mechanism of these metabolic inhibitors, we performed whole genome transcriptional analysis. Human SK-4 esophageal cancer cell lines were treated with 5 different treatment groups [2 deoxy glucose (4mM), Metformin (5mM), AICAR (2mM), 2 deoxy glucose (4mM) plus Metformin (5mM) and 2 deoxy glucose (4mM) plus AICAR (2mM)] with non treated control groups for 12 hrs. Each groups was quadruplicated. Microarray experiments and data analysis were done at Dept. of Systems Biology, MDACC (Houston, USA)
2012-12-31 | E-GEOD-16816 | biostudies-arrayexpress
Project description:Monocytes are the key mediators of inflammatory responses in virus patients, and are also the only blood cell type that supports productive infection both in vitro and in vivo. In this study, we assessed how dengue infection alters the metabolic response of monocytes and affects ensuing inflammatory mechanisms. Using a glycostress assay, we showed that in vitro infected primary human monocytes by dengue virus and monocytes isolated from thrombocytopenic dengue patients, during critical stage of the disease, had increased glycolysis. Single cell transcriptomics revealed an enhanced expression of interferon-related genes and glycolytic genes in classical and intermediate monocytes of dengue patients with more pronounced thrombocytopenia. Targeting glycolysis by 2-deoxy-glucose (2DG) reduced dengue infection and dampened pro-inflammatory cytokines in monocytes, both in vitro and in mouse models. Collectively, these results suggest that glycolysis could be a possible target for pharmaceutical intervention to regulate pathogenic host responses in dengue.
2021-04-02 | GSE171290 | GEO
Project description:Heparan sulfate (HS), a long linear polysaccharide, is implicated in various steps of tumorigenesis, including angiogenesis. We successfully interfered with HS biosynthesis using a peracetylated 4-deoxy analog of the HS constituent GlcNAc and studied the compound’s metabolic fate and its effect on angiogenesis. The 4-deoxy analog was activated intracellularly into UDP-4-deoxy-GlcNAc and HS expression was inhibited up to ~96% (IC50 = 16 µM). HS chain size was reduced, without detectable incorporation of the 4-deoxy analog, likely due to reduced levels of UDP-GlcNAc and/or inhibition of glycosyltransferase activity. Comprehensive gene expression analysis revealed reduced expression of genes regulated by HS binding growth factors as FGF-2 and VEGF. Cellular binding and signaling of these angiogenic factors was inhibited. Micro-injection in zebrafish embryos strongly reduced HS biosynthesis, and angiogenesis was inhibited in both zebrafish and chicken model systems. All these data identify 4-deoxy-GlcNAc as a potent inhibitor of HS synthesis which hampers pro-angiogenic signaling and neo-vessel formation.
2013-08-23 | GSE48284 | GEO
Project description:Heparan sulfate (HS), a long linear polysaccharide, is implicated in various steps of tumorigenesis, including angiogenesis. We successfully interfered with HS biosynthesis using a peracetylated 4-deoxy analog of the HS constituent GlcNAc and studied the compoundM-bM-^@M-^Ys metabolic fate and its effect on angiogenesis. The 4-deoxy analog was activated intracellularly into UDP-4-deoxy-GlcNAc and HS expression was inhibited up to ~96% (IC50 = 16 M-BM-5M). HS chain size was reduced, without detectable incorporation of the 4-deoxy analog, likely due to reduced levels of UDP-GlcNAc and/or inhibition of glycosyltransferase activity. Comprehensive gene expression analysis revealed reduced expression of genes regulated by HS binding growth factors as FGF-2 and VEGF. Cellular binding and signaling of these angiogenic factors was inhibited. Micro-injection in zebrafish embryos strongly reduced HS biosynthesis, and angiogenesis was inhibited in both zebrafish and chicken model systems. All these data identify 4-deoxy-GlcNAc as a potent inhibitor of HS synthesis which hampers pro-angiogenic signaling and neo-vessel formation. 9 samples were analyzed: 3 biological replicates from untreated SKOV3 cells, 3 biological replicates from SKOV3 cells treated with peracetylated GlcNAc, 3 biological replicates from SKOV3 cells treated with peracetylated 4-deoxy-GlcNAc
2013-08-23 | E-GEOD-48284 | biostudies-arrayexpress
Project description:The unfolded protein response (UPR) is a cellular defense mechanism against glucose deprivation, a cell condition that occurs in solid tumors. A key feature of the UPR is the activation of the transcription program that allows the cell to cope with endoplasmic reticulum (ER) stress. We used micoarrays to show that the UPR transcription program is disrupted by the antitumor macrocyclic compound versipelostatin (VST) and antidiabetic biguanides metformin, buformin and phenformin, depending on cellular glucose availability. Experiment Overall Design: Total 42 samples were prepared for RNA extraction and hybridization on Affymetrix microarrays. Experiment Overall Design: To induce the UPR, we treated cells (HeLa, HT-29, HT1080, MKN74) for 15 or 18 hours under ER stress conditions by replacing the medium with glucose-free medium or by adding either 2-Deoxy-D-glucose (2DG) or Tunicamycin (TM) to glucose-containing medium. UPR modulators (VST, biguanides or pyrvinium pamoate) were added at various final concentrations immediately after cells were placed in glucose-free medium or just before the chemical stressors were added to glucose-containing culture medium.
2009-06-01 | E-GEOD-13548 | biostudies-arrayexpress