Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA438922 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: Not available
| S-EPMC6327029 | biostudies-literature
Project description:We sought to determine whether Ldh activity in SCC tumors is a marker of the cell type from which these cells arise, or a key metabolic activity important for tumor initiation or progression. Here we show that genetic abrogation of Ldh enzyme activity in HFSC-mediated tumorigenesis had no effect on tumor number, time to tumor formation, tumor proliferation, epithelial to mesenchymal transition in tumors, gene expression in tumors, tumor pathology, or the immune response to tumors.
2018-12-04 | GSE111997 | GEO
Project description:We analyzed RNA levels in Drosophila Lactate Dehydrogenase mutants and precise excision controls during mid-L2 development.
2019-09-01 | GSE119334 | GEO
Project description:Corynebacterium glutamicum is able to grow with lactate as sole or combined carbon and energy source. Quinone-dependent L-lactate dehydrogenase LldD is known to be essential for utilization of L-lactate by C. glutamicum. D-lactate also serves as sole carbon source for C. glutamicum ATCC 13032. Here, the gene cg1027 was shown to encode the quinone-dependent D-lactate dehydrogenase (Dld) by enzymatic analysis of the protein purified from recombinant E. coli. The absorption spectrum of purified Dld indicated the presence of FAD as bound cofactor. Inactivation of dld resulted in the loss of the ability to grow with D-lactate, which could be restored by plasmid-borne expression of dld. Heterologous expression of dld from C. glutamicum ATCC 13032 in C. efficiens enabled this species to grow with D-lactate as sole carbon source. Homologs of dld of C. glutamicum ATCC 13032 are not encoded in the sequenced genomes of other corynebacteria and mycobacteria. However, the dld locus of C. glutamicum ATCC 13032 shares 2367 bp of 2372 bp identical nucleotides with the dld locus of Propionibacterium freudenreichii subsp. shermanii, a bacterium used in Swiss-type cheese making. Both loci are flanked by insertion sequences of the same family suggesting a possible event of horizontal gene transfer.
2010-12-02 | GSE25704 | GEO
Project description:In order to study the effect of lactate dehydrogenase (?ldh 1.2) mutant on the transcriptome DNA microarray technology was used. Stains were grown in a chemically defined medium (CDM-LAB) containing 1.1% of glucose as a carbon sources at 37?C on anaerobic condition to an optical density of 0.6.
2010-12-13 | E-MTAB-472 | biostudies-arrayexpress
Project description:Comparison of RNA expression between Drosophila Lactate Dehydrogenase mutants and controls
| PRJNA488802 | ENA
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:Interleukin (IL)-2 and IL-21 dichotomously shape CD8+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2–induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1. While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21–induced metabolism but caused major transcriptomic changes, including the suppression of IL-21–induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21.
2020-02-13 | GSE143903 | GEO
Project description:<p>Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl-coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.</p>
2023-08-07 | MTBLS7237 | MetaboLights
Project description:The “Warburg effect” describes the use of aerobic glycolysis by cancer cells to fuel their growth. Lactate dehydrogenase-A (LDHA) is key to this process and catalyzes the interconversion of pyruvate and lactate. Here we used a proteomic approach to identify LDHA as a binding partner of the tumor suppressor FLCN. Canonically, LDHA is thought to be a substrate-regulated enzyme, however our data show that FLCN uncompetitively inhibits LDHA activity by restricting movement of its active site loop. This inhibition appears to be critical in normal cells, as we show FLCN binds to and tightly regulates LDHA activity in order to preserve metabolic homeostasis. Pathogenic mutations of FLCN are associated with LDHA hyperactivity and kidney tumor formation, suggesting a mechanism for FLCN tumor suppressive function. We have identified a cell-permeant ten amino acid peptide based on the FLCN sequence that enters these tumors and inhibits LDHA ex vivo. In a broader context, renal cell carcinomas experience the Warburg effect and show FLCN dissociation from LDHA. Cells that experience this metabolic shift depend on the hyperactivity of LDHA, as previous work has shown attenuation or inhibition of LDHA leads to programmed cell death. Treating these cells with the FLCN-derived peptide causes apoptosis, strongly suggesting that the glycolytic shift of cancer cells is the result of FLCN inactivation or disassociation from LDHA. Taken together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
2021-08-05 | PXD018410 | Pride