Effects of Cyclic Acute and Chronic Hypoxia on Expression Level of Metabolism Related Genes in a Pancreatic Cancer Cell Line
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE207065 | GEO | 2022/06/28
REPOSITORIES: GEO
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Project description:Oxygen fluctuation during tissue remodeling imposes a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastomas are believed to possess extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. To identify adaptive response mechanism, we compared the effects of acute and chronic hypoxia versus oxygenation on stem-like glioblastoma (GS) cells. GS cell lines were established and propagated either under normoxia (21% O2) or hypoxia (1% O2) and subsequently exposed to acute normoxia or hypoxia, respectively. Gene expression profiling revealed that acute hypoxia predominantly induced metabolic pathways and cell cycle arrest, whereas chronic hypoxia activated neurodevelopmental processes. In particular, we found increased expression of glycolytic enzymes, especially of the preparatory phase of glycolysis, under acute hypoxia, whereas pentose phosphate pathway (PPP) enzymes were downregulated. The opposite was found for acute oxygenation of hypoxic GS cells. Findings were confirmed by qPCR and immunoblot analyses. Despite downregulation by hypoxia, expression of PPP enzymes is increased in GBMs compared to normal brain, whereas expression of hypoxia-inducible enzymes of the parallel preparatory phase of glycolysis is decreased. Immunohistochemistry revealed strong staining for PPP enzymes in the bulk of GBM tissue, especially in highly proliferative areas, but not in pseudopalisading (hypoxic) cells. Glycolytic enzymes displayed an inverse pattern. Mass spectrometric analysis using [1,2-13C2]-D-glucose showed reduced glucose flux through the PPP under hypoxia in favor of flux through glycolysis. Acute and chronic hypoxia increased cell migration but reduced proliferation, whereas normoxia had opposite effects. Our findings extend Warburg’s observations by showing that in most tumor cells the PPP, which supplies metabolites for biomass production, is favored over the parallel preparatory phase of glycolysis, but is suppressed under acute severe hypoxia, causing a switch to direct glycolysis to protect against hypoxic stress.
2020-12-31 | GSE45117 | GEO
Project description:Transcriptomics and functional bioinformatics were used to investigate the potential interactions of undernutrition and the presence of the conceptus at the time of maternal recognition of pregnancy on uterine indicators of metabolism and reproduction. Adult Rasa Aragonesa ewes were allocated to one of two planes of nutrition during 28 days: maintenance energy intake (control; 5 cyclic, 6 pregnant ewes) providing 7.8 MJ of metabolisable energy per ewe and 0.5 maintenance intake (undernourished; 6 cyclic, 7 pregnant ewes) providing 3.9 MJ of metabolisable energy per ewe. RNA from uterine tissue was harvested at slaughter on day 14 of estrus or pregnancy, and hybridized to the Agilent 15K Sheep Microarray chip. Functional bioinformatics analyses were performed using the Dynamic Impact Approach (DIA) and Ingenuity Pathway Analysis. Among metabolic pathways, citrate cycle, oxidative phosphorylation, pentose and glucuronate interconversions and biosynthesis of unsaturated fatty acids were upregulated in control pregnant compared with control cyclic ewes. However, these pathways were not altered in undernourished ewes. The presence of an embryo in undernourished ewes upregulated fatty acid and glycogenic amino acid metabolism. RIG-I and Toll like receptors and chemokine signaling pathways were upregulated by the presence of the embryo in both control and undernourished ewes, but in the latter group the impact was lower. Undernutrition alone upregulated carbohydrate metabolism, but different pathways were altered in cyclic versus pregnant ewes. Citrate cycle, glycolysis/gluconeogenesis, and pentose and glucuronate interconversions were upregulated in undernourished cyclic compared with control cyclic ewes. Glycolysis/gluconeogenesis, pyruvate and propanoate metabolism, beta-alanine and phenylalanine metabolism were upregulated in undernourished pregnant compared with control pregnant ewes, whereas biosynthesis of unsaturated fatty acids and replication and repair were downregulated. Undernutrition alone led to an overall weak activation of immune system pathways both in cyclic and pregnant ewes. However, undernourished cyclic compared with control cyclic ewes had a high activation of NOD-like and RIG-1 like receptor signaling pathways, whereas undernourished pregnant compared with control pregnant ewes only had a weak upregulation of T cell receptor signaling pathways. Overall, data revealed that metabolic and immune adaptations of the uterus to nutrient restriction are dependent on the presence of the conceptus.
2018-03-01 | GSE108176 | GEO
Project description:The initiation of heartbeat is an essential step in cardiogenesis in the heart primordium, but it remains unclear how intracellular metabolism responds to increased energy demands after heartbeat initiation. In this study, embryos in Wistar rats at embryonic day 10, at which heartbeat begins in rats, were divided into two groups by the heart primordium before and after heartbeat initiation and their metabolic characteristics were assessed. Metabolome analysis revealed that increased levels of ATP, a main product of glucose catabolism, and reduced glutathione, a by-product of the pentose phosphate pathway, were the major determinants in the heart primordium after heartbeat initiation. Glycolytic capacity and ATP synthesis-linked mitochondrial respiration were significantly increased, but subunits in complexes of mitochondrial oxidative phosphorylation were not upregulated in the heart primordium after heartbeat initiation. Hypoxia-inducible factor (HIF)-1α was activated and a glucose transporter and rate-limiting enzymes of the glycolytic and pentose phosphate pathways, which are HIF-1α-downstream targets, were upregulated in the heart primordium after heartbeat initiation. These results suggest that the HIF-1α-mediated enhancement of glycolysis with activation of the pentose phosphate pathway, potentially leading to antioxidant defense and nucleotide biosynthesis, covers the increased energy demand in the beating and developing heart primordium.
2021-10-14 | GSE185702 | GEO
Project description:Background: Hypoxia can affect aerobic organisms profoundly. Biological responses to extreme hypoxia have been well studied. However, it is not well characterized how living organisms respond to mild hypoxia, and how they distinguish different levels of hypoxia. Results: We examined the transcriptional responses of locusts using microarrays to reveal their strategies to cope with mild hypoxia. Mitochondrial activities were systemically suppressed, mainly involving energy production and mitochondrial biogenesis. The functions of endoplasmic reticulum were activated to clear the dysfunctional proteins and rescue newly synthesized proteins. Glucose in cytosol was shunted from glycolysis to pentose phosphate pathway probably to tackle the oxidative stress by enhancing the production of reductive forces. Conclusions: LocustsM-bM-^@M-^Y responses to mild hypoxia differ from that to severe hypoxia . In severe hypoxia, glucose resources are shunted to glycolysis to produce ATP and tackle energy crisis; however, in mild hypoxia, they are diverted to produce reductive forces and deal with oxidative stress. Locusts are capable of distinguishing different levels of hypoxia and initiating proper defenses. Simulated 4km altitude hypoxia treatment vs. normoxia control;direct comparison on 6 separate microarrays; each microarray compares one biological replicate of treatment and control; each biological replicate contains 10 individuals
2012-12-12 | E-GEOD-33898 | biostudies-arrayexpress
Project description:Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia. We found that HIF-1 also actively suppresses glucose metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1α-null cells increases ATP levels, attenuates hypoxic ROS generation and rescues these cells from hypoxia-induced apoptosis. These studies reveal a novel hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production. Experiment Overall Design: We sought to determine by microarray analysis of gene expression the genes responsive to hypoxia using the human B lymphocyte cell line, P493-6. Hypoxia-responsive genes were globally assessed in cells incubated in 0.1% O2 for 29 hours at which the highest HIF-1 levels were obtained
2008-06-12 | E-GEOD-4086 | biostudies-arrayexpress
Project description:Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia. We found that HIF-1 also actively suppresses glucose metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1α-null cells increases ATP levels, attenuates hypoxic ROS generation and rescues these cells from hypoxia-induced apoptosis. These studies reveal a novel hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production. Keywords: Hypoxia responsive, case control
2006-03-16 | GSE4086 | GEO
Project description:Background: Hypoxia can affect aerobic organisms profoundly. Biological responses to extreme hypoxia have been well studied. However, it is not well characterized how living organisms respond to mild hypoxia, and how they distinguish different levels of hypoxia. Results: We examined the transcriptional responses of locusts using microarrays to reveal their strategies to cope with mild hypoxia. Mitochondrial activities were systemically suppressed, mainly involving energy production and mitochondrial biogenesis. The functions of endoplasmic reticulum were activated to clear the dysfunctional proteins and rescue newly synthesized proteins. Glucose in cytosol was shunted from glycolysis to pentose phosphate pathway probably to tackle the oxidative stress by enhancing the production of reductive forces. Conclusions: Locusts’ responses to mild hypoxia differ from that to severe hypoxia . In severe hypoxia, glucose resources are shunted to glycolysis to produce ATP and tackle energy crisis; however, in mild hypoxia, they are diverted to produce reductive forces and deal with oxidative stress. Locusts are capable of distinguishing different levels of hypoxia and initiating proper defenses.
2012-12-12 | GSE33898 | GEO
Project description:This model is described in the article:
Glucose 6-phosphate accumulates via phosphoglucose isomerase inhibition in heart muscle.
Karlstaedt, A and Khanna, R and Thangam, M and Taegtmeyer, H
Circulation Research (2019)
The model describes glycolysis (including pyruvate oxidation and ATP turnover) in cardiomyocytes. An extension of the same model includes the pentose phosphate pathway.
2019-11-14 | MODEL1910170001 | BioModels
Project description:Tumor hypoxia is not a stable phenomenon but cycles between periods of deep hypoxia and reoxygenation. Cyclic hypoxia originates from heterogeneities in red blood cell flux and from the permanent remodelling of the angiogenic vascular network. Endothelial cells lining tumor blood vessels are therefore also influenced by cyclic hypoxia. The gene expression pattern promoted by cyclic hypoxia differs from those observed under normoxia and even continuous hypoxia. PTGS2 is one gene exquisitely up-regulated in endothelial cells (and tumor cells) in response to cyclic hypoxia. Elevated COX-2 (the PTGS2 gene product) expression and activity account for cyclic hypoxia-driven increase in endothelial cell survival and angiogenesis.
2009-12-24 | GSE12246 | GEO
Project description:Previous findings have demonstrated that the NADH/NAD+ ratio has a strong impact on the glycolytic flux in C. glutamicum under anaerobic conditions in the absence of external electron acceptors. During an attempt to rewire anaerobic metabolism to achieve high yield formation of ethanol, we inactivated the malate dehydrogenase and lactate dehydrogenase in a C. glutamicum strain expressing pyruvate decarboxylase and alcohol dehydrogenase, to eliminate formation of the by-products succinate and lactate, respectively. This modification increased the yield of ethanol but had a negative effect on glycolysis, which we found to correlate with an elevated NADH/NAD+ ratio. The pyruvate dehydrogenase (PDH) of C. glutamicum is active under anaerobic conditions, and can potentially exacerbate the negative effect on glycolysis, due to NADH formation. To reduce PDH activity under anaerobic conditions, we decided to replace the gene encoding the E3 subunit of PDH with its Escherichia coli counterpart, as E. coli PDH has been reported to be functional under aerobic conditions only. The resultant strain JS133 produced far less acetate with a further increased ethanol production, however, the glycolytic flux was still low. After observing differences in glycolytic flux for JS133 on glucose and fructose, we speculated that the pentose phosphate pathway (PPP) might be involved in the reduced flux on glucose. To prove this, we deleted the zwf gene, encoding glucose-6-phosphate dehydrogenase, which is the entry point into PPP, and immediately observed a stimulating effect on glycolysis. Subsequent characterization revealed a direct correlation between the intracellular NADH/NAD+ and NADPH/NADP+ ratios under anoxic conditions. Based on these findings we managed to re-channel the metabolism of C. glutamicum successfully towards either to ethanol or D-lactate with 92% and 98% of the theoretical yield respectively, which is the highest yields for D-lactate production thus far reported in the literature.
2020-10-02 | GSE143977 | GEO