NPM-ALK metabolic regulation
Ontology highlight
ABSTRACT:
ORGANISM(S): Human Homo Sapiens
TISSUE(S): Lymphoma Cells
SUBMITTER: 
Scott McDonnell
PROVIDER: ST000016 | MetabolomicsWorkbench | Tue Sep 24 00:00:00 BST 2013
REPOSITORIES: MetabolomicsWorkbench
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| mwtab | Other |
Items per page: 5 1 - 1 of 1 |
Similar Datasets
Project description:Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades anti-tumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming towards glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of microglial phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) P300 to induce increased P300 substrate specificity toward lactyl-coA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates a metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immune-oncology therapies.
2023-10-26 | GSE245854 | GEO
Project description:Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades anti-tumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming towards glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of microglial phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) P300 to induce increased P300 substrate specificity toward lactyl-coA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates a metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immune-oncology therapies.
2023-10-26 | GSE245853 | GEO
Project description:Microenvironment is known to influence cancer drug response and sustain resistance to therapies targeting receptor-tyrosine kinases. However if and how tumor microenvironment can be altered during treatment, contributing to resistance onset is not known. Here we show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift towards increased glycolysis and lactate production. We identified secreted lactate as the key molecule able to instruct Cancer Associated Fibroblasts (CAFs) to produce Hepatocyte Growth Factor (HGF) in a NF-KB dependent manner. Increased HGF, activating MET-dependent signaling in cancer cells, sustained resistance to TKIs. Functional targeting or pharmacological inhibition of lactate dehydrogenase prevented and overcame in vivo resistance, demonstrating the crucial role of this metabolite in the adaptive process. This non-cell-autonomous, adaptive resistance mechanism was observed in NSCLC patients progressed on EGFR TKIs, demonstrating the clinical relevance of our findings and opening novel scenarios in the challenge to drug resistance
2018-07-06 | GSE115172 | GEO
Project description:Metformin-induced lactate production can lead to lactate acidosis as life-threatening side effect, whereas lactate in a physiological range might also be involved in the therapeutic effect. How metformin increases systemic lactate concentrations is only partly understood. Since human skeletal muscle has a high capacity to produce lactate, we aim to elucidate the potential contribution of skeletal muscle and the dose-dependent regulation of metformin-induced lactate production in primary human myotubes after 48 h of metformin treatment (16-776 μM). At 78 µM, metformin induced lactate production and glucose consumption. Investigating the cellular redox state by mitochondrial respirometry, we found metformin to inhibit the respiratory chain complex I (776 µM, p<0.01) along with a decreased [NAD+]:[NADH] ratio (776 µM, p<0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation mediated through phosphorylation of PDH complex (39 µM, p<0.01). In vivo in human skeletal muscle, we found pyruvate metabolism altered by exercise and not by metformin. Nonetheless, blood lactate levels in the pre-exercise condition are increased under metformin treatment (p<0.05). Metformin-induced inhibition of pyruvate oxidation combined with altered cellular redox state, both shift the equilibrium of the LDH reaction leading to enhanced lactate production of human myotubes.
2023-09-04 | GSE229658 | GEO
Project description:In this study, we sought to investigate the metabolic role of MALAT1, one of the most abundant cancer-associated long non-coding RNA, in prostate cancer. MALAT1 targeting by gapmerization reduced expression of some tricarboxylic acid cycle enzymes including the malic enzyme 3 and the pyruvate dehydrogenase kinases 1 and 3 as well as the choline kinase A. In consequence, prostate cancer metabolism switched toward a glycolytic phenotype characterized by increased lactate production paralleled by growth arrest, and cell death. Conversely, the function of mitochondrial succinate dehydrogenase and expression of oxphos enzymes was markedly reduced, suggesting for a decreased tricarboxylic acid cycle and mitochondrial respiration activity. Interestingly, a similar effect was observed in several prostate cancer-derived organotypic slice cultures, in which metabolism became more glycolytic and apoptotic. Based on these observations, we elaborated a predictive algorithm, in which those metabolic enzymes sensitive to MALAT1 targeting proven successfully to predict tumor recurrence in a subset of patients. In summary, MALAT1 targeting by gapmerization activates a metabolic switch in the prostate cancer cell and tumor tissue unraveling a role for crucial metabolic enzymes in tumor progression and outcome.
2021-07-30 | GSE147566 | GEO
Project description:Purpose: Myxopapillary ependymoma (MPE) is a distinct histological variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Experimental Design: Gene expression profiling was performed on 35 spinal ependymomas. Functional validation experiments were performed on tumour lysates consisting of assays measuring Pyruvate Kinase M activity (PKM), Hexokinase activity (HK), and lactate production. Results: At a gene expression level, we demonstrate that spinal Grade II and MPE are molecularly and biologically distinct. These findings are supported by specific copy number alterations occurring in each histological variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with up-regulation of HIF-1α. These findings were validated by western blot analysis demonstrating increased protein expression of HIF-1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Conclusions: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE. RNA from 35 primary spinal ependymomas (fresh frozen) were isolated by pulverization in liquid nitrogen, and extraction using the Trizol Method (Invitrogen) [PMID:21840481]
2015-09-02 | E-GEOD-66787 | biostudies-arrayexpress
Project description:Synaptic activity drives changes in gene expression to promote long-lasting adaptations of neuronal structure and function. One example of such an adaptive response is the buildup of acquired neuroprotection, a synaptic activity- and gene transcription-mediated increase in the resistance of neurons against harmful conditions. A hallmark of acquired neuroprotection is the stabilization of mitochondrial structure and function. We therefore re-examined previously identified sets of synaptic activity-regulated genes to identify genes that are directly linked to mitochondrial function. In mouse and rat primary hippocampal cultures synaptic activity caused an upregulation of glycolytic genes and a concomitant downregulation of genes required for oxidative phosphorylation, mitochondrial biogenesis and maintenance. Changes in metabolic gene expression were induced by action potential bursting, but not by glutamate bath application activating extrasynaptic NMDA receptors. The specific pattern of gene expression changes suggested that synaptic activity promotes a shift of neuronal energy metabolism from oxidative phosphorylation toward aerobic glycolysis, also known as Warburg effect. The ability of neurons to upregulate glycolysis has, however, been debated. We therefore used FACS sorting to show that, in mixed neuron glia co-cultures, activity-dependent regulation of metabolic gene expression occurred in neurons. Changes in gene expression were accompanied by changes in the phosphorylation-dependent regulation of the key metabolic enzyme, pyruvate dehydrogenase. Finally, increased synaptic activity caused an increase in the ratio of L-lactate production to oxygen consumption in primary hippocampal cultures. Based on these data we suggest the existence of a synaptic activity-mediated neuronal Warburg effect that may promote mitochondrial homeostasis and neuroprotection.
2017-02-28 | GSE92275 | GEO
Project description:Plant biomass is the most abundant and renewable carbon source for many fungal species. The composition of biomass consists of about 40-45% cellulose, 20-30% hemicellulose, and 15-25% lignin and varies among plant species. In the bio-based industry, Aspergillus species and other fungi are used for the production of lignocellulolytic enzymes to pretreat agricultural waste biomass (e.g. wheat bran). In this study, we aimed to evaluate if it would be possible to create an Aspergillus strain that releases but does not metabolize hexoses from plant biomass. For this purpose, metabolic mutants were generated that were (partially) impaired in glycolysis, by deleting the hexokinase (hxkA) and glucokinase (glkA) genes. To prevent repression of enzyme production due to the accumulation of hexoses, strains were generated in which these mutations were combined with a mutation in creA, encoding the repressor involved in carbon catabolism. Phenotypic analysis revealed that growth of the ΔhxkAΔglkA mutant was reduced on wheat bran. However, hexoses did not accumulate during growth of the mutants on wheat bran, suggesting that glucose metabolism is re-routed towards alternative carbon catabolic pathways. Deletion of creA combined with blocking glycolysis resulted in an increased expression of pentose catabolic and phosphate pathway genes. This indicates that the reduced ability to use hexoses as carbon sources has resulted in a shift towards the pentose fraction of wheat bran as a major carbon source to support growth.
2018-02-26 | GSE94775 | GEO
Project description:Low intracellular folate levels diminish the growth rate of HT-29 human colon cancer cells. This is accompanied by a metabolic shift from cytosolic glycolysis towards mitochondrial oxidative phosphorylation, as demonstrated by a lower lactate production and an increased mitochondrial oxygen consumption rate. To obtain insight in the molecular effects underlying these changes, the steady state gene expression profiles of HT-29 cells with different intracellular folate concentrations were compared. The gene expression profile of HT-29 cells with low intracellular folate levels (grown for 3 weeks in 10 ng/ml folic acid (PGA)) was clearly distinct from that of the other exposure conditions, which provide sufficient intracellular folate levels (100 ng/ml PGA, 10 ng/ml methyltetrahydrofolate (MTHF) or 100 ng/ml MTHF). Intracellular folate deficiency, contrary to expectation, did not lead to major changes in expression of genes involved in energy metabolism. This suggests that the shift towards mitochondrial oxidative phosphorylation is not mediated at the transcription level. Furthermore, only minor changes in the expression of folate metabolism related genes were observed. The changes that were observed were consistent with nucleotide salvage and in agreement with nucleotide need of the slow-growing folate-deficient HT-29 cells. The major observed effects were on cell cycle related gene expression, which was increased and interferon-responsive gene expression, which was reduced. The increase in cell cycle related gene expression seems compensatory to the reduced cell growth. Down-regulation of the interferon-response may be explained by decreased expression of signal transducer and activator of transcription 1 upon folate deficiency. Keywords: dose response, folic acid, HT-29 cells, human
2005-08-13 | GSE3099 | GEO
Project description:During early post-natal stage, cardiomyocytes undergo dramatic structural, metabolic, electrophysiological and cell cycle alterations towards maturation. Among them, the metabolic shift from carbohydrates to fatty acids metabolism is achieved along with mitochondrial biogenesis, dynamic switch and mitophagy. However, the regulatory mechanisms responsible for coordinated mitochondrial dynamics and mitophagy in mitochondrial maturation remain unclear. Here, we found that ablation of PDK1 in post-natal cardiomyocytes impairs mitochondrial maturation and metabolism, characterizing by arrest of mitochondria in neonatal stage, low levels of a subset of fatty acids and acylcarnitines. In addition, loss of PDK1 results in dysregulated mitochondrial dynamics and mitophagy. An imbalance of the AMPK-mTOR pathway and reduced phosphorylation of PDK1 substrates, including PKA and PKC family members, are observed. These results demonstrated that PDK1 ensures mitochondrial maturation and metabolic shift through kinase-dependent substrate phosphorylation and maintenance of the AMPK-mTOR axis to coordinate mitochondrial dynamics and mitophagy.
2023-08-01 | GSE215056 | GEO