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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Compound C prevents the unfolded protein response during glucose deprivation through a mechanism independent of AMPK and BMP signaling.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Akihiro Tomida

PROVIDER: E-GEOD-32911 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription profiling of human cancer cells treated with unfolded protein response modulators under endoplasmic reticulum stress conditions

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

Compound C prevents the unfolded protein response during glucose deprivation through a mechanism independent of AMPK and BMP signaling.

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.

2012-10-11 | GSE32911 | GEO

Microarray expression data of HT-29 cells treated with spautin-1 or buformin under 2DG- or tunicamycin-stressed conditions

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

Expression data from human cancer cells treated with UPR modulators under ER stress conditions

2009-05-20 | GSE13548 | GEO

Mitochondria help avoid glucose addiction in cancer cells

Project description:Cancer cells consume large amounts of glucose because of their specific metabolic pathway. However, cancer cells exist in tumor tissue where glucose is insufficient. To survive, cancer cells likely have the mechanism to elude their glucose addiction. Here we show that functional mitochondria are essential if cancer cells are to avoid glucose addiction. Cancer cells with dysfunctional mitochondria, such as mitochondrial DNA-deficient rho0 cells and electron transport chain blocker-treated cells, were highly sensitive to glucose deprivation. Our data demonstrated that this sensitization was caused by failure of the unfolded protein response (UPR), an adaptive response mediated by the endoplasmic reticulum (ER). This study suggests a link between mitochondria and the ER during the UPR under glucose deprivation conditions and that mitochondria govern cell fate, not only through ATP production and apoptosis regulation but also through modulating the UPR for cell survival. Human cancer cell lines (HT-1080, HT-29, and mtDNA-deficient cells derived from these cell lines) were selected for RNA extraction and hybridization on Affymetrix microarrays. We examined the unfolded protein response (UPR), an adaptive response mediated by the endoplasmic reticulum (ER), of cancer cells under stress conditions. Abbreviations List: AA, antimycin A; Bu, buformin; Met, metformin; Phen, phenformin; Rot, rotenone; VST, versipelostatin; TM, tunicamycin; 2DG, 2-deoxyglucose; GS, glucose starvation. Capital S (_S) indicates the supernatant of sample including floating cells.

2010-05-28 | E-GEOD-16157 | biostudies-arrayexpress

Proteomic response of yeast cells to 2-deoxyglucose exposure (0.2%, 2.5h)

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

Proteomic analysis of mouse hearts treated with and without 2-deoxy-D-glucose

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

Transcriptional profiling of Ampk-deficient B cells during terminal differentiation

Project description:5’-AMP-Activated Protein Kinase (Ampk) is an energy gatekeeper that responds to decreases in available ATP by inhibiting energy-consuming processes like protein synthesis and promoting energy-generating processes like glucose uptake. Recently, our lab showed that Lkb1, a previously unstudied kinase in B cell immunology and the main upstream kinase of Ampk, had a critical and unexpected role in B cell activation and germinal center formation. In T cells knockout of the downstream target Ampk, only partially phenocopies Lkb1 deletion, so we sought to determine whether the role of Lkb1 in B cells depends on Ampk. We find Ampk is activated upon B cell stimulation in vitro. Surprisingly, however, Ampk activation occurs in the absence of energetic stress, and B cells continue to grow and divide despite Ampk activity. We performed an IP-MS substrate screen to identify Ampk targets and only identified a limited repertoire of canonical targets, and many non-canonical targets. Despite activation of Ampk and the major role of Lkb1 in B cell activation, B cell specific deletion of Ampk does not significantly affect B cell activation, differentiation, carbon handling, gene expression, or humoral immune responses. The only major effect of Ampk loss was accelerated downregulation of IgD during stimulation, which was preceded by downregulation of the IgD regulator Zfp318. Early activation of Ampk by pharmacological means also has little impact on B cell function, although treatment with the biguanide Phenformin critically impairs germinal center formation and class switch recombination in vivo, but does not significantly impair antigen-specific antibody responses. Combined, our results suggest an unexpected and unexplained activation of Ampk in B cells.

2019-06-16 | GSE121025 | GEO

Transcriptional profiing of cultured adherent and non-adherent monocytes

Project description:To determine the effect of adherence on the metabolic and functional response of human monocytes. Monocytes were stimulated with lipopolysaccharide (LPS) under non-adherent and adherent conditions. To determine the role of glycolysis in LPS-induced immune responses, this pathway was inhibited by glucose deprivation or the glucose analog 2-deoxy-D-glucose (2DG).

2020-12-08 | GSE161839 | GEO

Glycosylation-dependent modulation of the IL-2 signaling axis determines Th17 differentiation and IL-10 production

Project description:Metabolism plays an essential role in shaping Th cell responses including the production of pro-inflammatory cytokines. However, its effect on the production of the anti-inflammatory cytokine IL-10 has not been investigated. We show here that the glucose analogue 2-deoxyglucose (2DG) specifically inhibited Th1 and Th2 cell differentiation and accompanying IL-10 production. In contrast, 2DG promoted IL-17A production by Th17 cells, even in the presence of IL-2 known to limit Th17 differentiation, whilst simultaneously also abrogating the production of IL-10. Rather than inhibiting glycolysis, 2DG was found to act through the inhibition of glycosylation, itself critical for IL-2Ra surface expression and downstream signaling, explaining the reciprocal effect of 2DG on the Th1 and Th2 versus Th17 differentiation. The essential role of IL-2 for IL-10 production by Th17 cells was confirmed by adding IL-2 or anti-IL-2, neither of which made the cells more pathogenic. The molecular mechanism of the IL-2 driven Th17 IL-10 production may be attributed to the transcription factor c-Maf, whose expression was significantly upregulated in the presence of IL-2 signaling. The overall RNA signature of sorted IL-10+ T cells driven by IL-2, be it IL-17A+ or IL-17A-, was dominated by protein synthesis whereas that of their IL-10- counterparts by cell cycle associated processes suggesting that IL-10 secreting Th17 cells trade off self-renewal for secretory capacity. Our study thus reveals a previously unappreciated, anti-inflammatory role for IL-2 in Th17 cell production of IL-10 and identifies a novel mechanism to limit Th17 pathogenicity.

2020-03-29 | GSE129028 | GEO

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