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Combinatorial targeting of glycolysis and oxidative phosphorylation suppresses tumor growth and metastases.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE16816 | GEO | 2012/12/31

SECONDARY ACCESSION(S): PRJNA117595

REPOSITORIES: GEO

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Combinatorial targeting of glycolysis and oxidative phosphorylation suppresses tumor growth and metastases.

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

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

Selective effects of long-term glycolytic inhibition on B cells from autoimmune prone mice

Project description:To determine the metabolic requirements of key autoimmune populations in a spontaneous lupus-prone mouse model, we carried out RNA-seq of BXSB.Cg-Cd8atm1Mak Il15tmImx Yaa (Yaa DKO) mice following glycolytic inhibition with 2-deoxyglucose (2DG). Pre-symptomatic (6-week old) mice were used as controls for symptomatic (10-week old) mice with or without long-term (4-week) treatment with 2DG. As a result, we found that 2DG-mediated glycolytic inhibition preferentially affected gene signatures of activated B cells and not T cells or other immune cell populations.

2024-02-23 | GSE224148 | GEO

Starvation and chemotherapy

Project description:Tumor chemoresistance is often associated to high aerobic glycolysis rates and reduced oxidative phosphorylation by cancer cells, a phenomenon called the “Warburg effect”. Thus, a treatment reversing the Warburg effect could decrease tumor cell survival both in the presence or absence of chemotherapy. Short-term starvation (STS) could accomplish this task since it is accompanied by a glucose and amino acid decrease and fatty acid increase, which require respiration for energy production. We tested the cytotoxicity of STS+Oxaliplatin on colon cancer cells by Trypan Blue, Carboxyfluorescein Succinimidyl ester and Annexin V staining. Reactive oxygen species production was measured by 2',7'-dichlorodihydrofluorescein diacetate staining. In vitro glucose consumption was evaluated by 18F-Fluoro-deoxyglucose uptake. Gene expression was tested by microarray analysis. Protein expression and activity were studied by western blot, proteomic analyses and spectrophotometric assays. CT26 bearing mice consumed only water for 48 hours (STS) before oxaliplatin treatment. Dynamic micro-Positron Emission Tomography and tumor growth measurements were performed. STS+Oxaliplatin cause a potent suppression of colon carcinoma growth and glucose consumption in in vitro and in vivo models. In CT26 cells, STS down-regulates aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. STS-dependent increase in O2 consumption is associated with reduced ATP synthesis and increased oxidation. In combination with chemotherapy, these effects of STS cause additive toxicity to cancer cells. Our findings indicate that during and following STS the decreased glucose levels promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis. The experiment comprised for conditions: Control, Starvation, Oxaliplatin, and Starvation plus Oxaliplatin

2015-08-11 | E-GEOD-60653 | biostudies-arrayexpress

SIRT3 opposes metabolic reprogramming of cancer cells through HIF1a destabilization

Project description:Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates and redox potential required for the generation of biomass. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. SIRT3 loss promotes a metabolic profile consistent with high glycolysis required for anabolic processes in vivo and in vitro. Mechanistically, SIRT3 mediates metabolic reprogramming independently of mitochondrial oxidative metabolism and through HIF1a, a transcription factor that controls expression of key glycolytic enzymes. SIRT3 loss increases reactive oxygen species production, resulting in enhanced HIF1a stabilization. Strikingly, SIRT3 is deleted in 40% of human breast cancers, and its loss correlates with the upregulation of HIF1a target genes. Finally, we find that SIRT3 overexpression directly represses the Warburg effect in breast cancer cells. In sum, we identify SIRT3 as a regulator of HIF1a and a suppressor of the Warburg effect. RNA isolated from brown adipose tissue of SIRT3 WT and KO mice. 5 wild-type samples and 5 SIRT3 KO samples

2011-03-15 | E-GEOD-27309 | biostudies-arrayexpress

Xenopus tropicalis glycolysis and PPP inhibition

Project description:Stage 41 tadpoles were injected with 4 nmol of the glycolysis inhibitor, 2-deoxyglucose (2DG), or a tracer control to evaluate consequences of inhibition on metabolites 24 hours after treatment began. Similarly, tadpoles were incubated in DMSO control or 1 of 2 G6PD inhibitors (Dehydroepiandrosterone and g6pdi), to similarly assess the consequences of inhibiting the pentose phosphate pathway. We find that inhibition of glucose metabolism with 2DG results in a decrease in downstream glycolytic intermediates, confirming a reduction in activity of this pathway. G6PD inhibition was not as clear as changes were less consistent across treatments and downstream metabolites did not behave in a coordinated way, though impacts on other metabolic processes by these inhibitors may be fruitful for exploring how they perturb metabolism in the tadpoles.

2022-08-03 | ST002270 | MetabolomicsWorkbench

Expression data from the dorsal and lateral lobes of the prostates of TRAMP mice treated with OSU-CG5

2013-01-06 | GSE32422 | GEO

ADDITIVE EFFECTS OF MILLIMETER WAVES AND 2 DEOXYGLUCOSE CO-EXPOSURE ON THE HUMAN KERATINOCYTE TRANSCRIPTOME

Project description:To evaluate the effect of millimeter waves (MMW) exposure on the gene expression, we have employed whole genome microarray expression profiling. Neonatal primary Keratinocyte cells pooled from 3 healthy donors were exposed ex vivo, by 60.4 GHz-MMW, at an incident power density (IPD) of 20 mW/cm² (3 hours of treatment in athermic condition).No modification of keratinocyte transcriptome was observed. Considering that MMW could also impact the cell metabolism, we assessed then effect of glycolysis inhibitor 2 deoxyglucose treatment (2dG, 20 mM during 3 hours) in association with MMW co-exposure. 2dG treatment induces a high modification of the transcriptome (632 coding genes). Genes affected in their expression are linked with transcriptional repression, cellular communication and endoplasmic reticulum homeostasis. The MMW/2dG co-exposition induced a slight modification of cell transcriptome, which reflects the capacity of MMW to interfere with bioenergetic stress response. After RT-PCR validation, 6 genes (SOCS3, SPRY2, TRIB1, FAM46A, CSRNP1 and PPP1R15A) were confirmed as sensitive to MMW exposure during 2dG treatment.

2016-09-20 | GSE83829 | GEO

Expression data from the dorsal and lateral lobes of the prostates of TRAMP mice treated with OSU-CG5

Project description:Cells undergoing malignant transformation often shift their cellular metabolism from primarily oxidative phosphorylation to aerobic glycolysis (the Warburg effect). Energy restriction-mimetic agents (ERMAs), such as 2-deoxyglucose and resveratrol, that target this shift in cellular metabolism have been effective in inhibiting cancer cell growth in vitro, and xenograft tumor growth in vivo. We recently developed a novel ERMA, OSU-CG5, that exhibits higher in vivo activity than previously described ERMAs. In this study, we investigated the effect of OSU-CG5 on global gene expression in the dorsal and lateral lobes of the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, and on its ability to suppress lesion progression in these mice. Intact male TRAMP mice were randomized into 2 groups and treated for 4-weeks (from age 6 to 10 weeks) with a vehicle or 100 mg/kg/day OSU-CG5 via oral gavage. At the end of the study, the urogenital tracts were collected and prostates microdissected. RNA was extracted from the dorsal and lateral lobes of the prostates from 3 mice per group, and Affymetrix microarrays were performed.

2013-01-06 | E-GEOD-32422 | 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. 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

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