The Warburg effect is genetically determined in inherited pheochromocytomas.
Ontology highlight
ABSTRACT:
SUBMITTER: Favier J
PROVIDER: S-EPMC2738974 | biostudies-literature | 2009 Sep
REPOSITORIES: biostudies-literature
Publications
The Warburg effect is genetically determined in inherited pheochromocytomas.
Favier Judith J Brière Jean-Jacques JJ Burnichon Nelly N Rivière Julie J Vescovo Laure L Benit Paule P Giscos-Douriez Isabelle I De Reyniès Aurélien A Bertherat Jérôme J Badoual Cécile C Tissier Frédérique F Amar Laurence L Libé Rosella R Plouin Pierre-François PF Jeunemaitre Xavier X Rustin Pierre P Gimenez-Roqueplo Anne-Paule AP
PloS one 20090918 9
The Warburg effect describes how cancer cells down-regulate their aerobic respiration and preferentially use glycolysis to generate energy. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. SDH and VHL gene mutations have been shown to lead to the activation of hypoxic response, even in normoxic conditions, a process now referred to a ...[more]
Similar Datasets
Project description:Lactate is shuttled between and inside cells, playing metabolic and signaling roles in healthy tissues. Lactate is also a harbinger of altered metabolism and participates in the pathogenesis of inflammation, hypoxia/ischemia, neurodegeneration and cancer. Many tumor cells show high rates of lactate production in the presence of oxygen, a phenomenon known as the Warburg effect, which has diagnostic and possibly therapeutic implications. In this article we introduce Laconic, a genetically-encoded Forster Resonance Energy Transfer (FRET)-based lactate sensor designed on the bacterial transcription factor LldR. Laconic quantified lactate from 1 µM to 10 mM and was not affected by glucose, pyruvate, acetate, betahydroxybutyrate, glutamate, citrate, ?-ketoglutarate, succinate, malate or oxalacetate at concentrations found in mammalian cytosol. Expressed in astrocytes, HEK cells and T98G glioma cells, the sensor allowed dynamic estimation of lactate levels in single cells. Used in combination with a blocker of the monocarboxylate transporter MCT, the sensor was capable of discriminating whether a cell is a net lactate producer or a net lactate consumer. Application of the MCT-block protocol showed that the basal rate of lactate production is 3-5 fold higher in T98G glioma cells than in normal astrocytes. In contrast, the rate of lactate accumulation in response to mitochondrial inhibition with sodium azide was 10 times lower in glioma than in astrocytes, consistent with defective tumor metabolism. A ratio between the rate of lactate production and the rate of azide-induced lactate accumulation, which can be estimated reversibly and in single cells, was identified as a highly sensitive parameter of the Warburg effect, with values of 4.1 ± 0.5 for T98G glioma cells and 0.07 ± 0.007 for astrocytes. In summary, this article describes a genetically-encoded sensor for lactate and its use to measure lactate concentration, lactate flux, and the Warburg effect in single mammalian cells.
| S-EPMC3582500 | biostudies-literature
Project description:A glycolytic profile unifies a group of pheochromocytomas and paragangliomas (PHEOs/PGLs) with distinct underlying gene defects, including von Hippel-Lindau (VHL) and succinate dehydrogenase B (SDHB) mutations. Nevertheless, their tumor aggressiveness is distinct: PHEOs/PGLs metastasize rarely in VHL-, but frequently in SDHB-patients. To date, the molecular mechanisms causing the more aggressive phenotype in SDHB-PHEOs/PGLs remain largely unknown. Recently, however, an excellent model to study aggressive PHEOs (mouse tumor tissue (MTT) cells) has been developed from mouse PHEO cells (MPC). We employed this model for a proteomics based approach to identify changes characteristic for tumor aggressiveness, which we then explored in a homogeneous set of human SDHB- and VHL-PHEOs/PGLs. The increase of glucose transporter 1 in VHL, and of hexokinase 2 in VHL and SDHB, confirmed their glycolytic profile. In agreement with the cell model and in support of decoupling of glycolysis, the Krebs cycle and oxidative phosphorylation (OXPHOS), SDHB tumors showed increased lactate dehydrogenase levels. In SDHB-PGLs OXPHOS complex activity was increased at complex III and, as expected, decreased at complex II. Moreover, protein and mRNA expression of all tested OXPHOS-related genes were higher in SDHB- than in VHL-derived tumors. Although there was no direct evidence for increased reactive oxygen species production, elevated superoxide dismutase 2 expression may reflect elevated oxidative stress in SDHB-derived PHEOs/PGLs. For the first time, we show that despite dysfunction in complex II and evidence for a glycolytic phenotype, the Warburg effect does not seem to fully apply to SDHB-PHEOs/PGLs with respect to decreased OXPHOS. In addition, we present evidence for increased LDHA and SOD2 expression in SDHB-PHEOs/PGLs, proteins that have been proposed as promising therapeutic targets in other cancers. This study provides new insight into pathogenic mechanisms in aggressive human PHEOs/PGLs, which may lead to identifying new diagnostic and prognostic markers in the near future.
| S-EPMC3409208 | biostudies-literature
Project description:BACKGROUND:The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS:We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS:We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS:There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).
| S-EPMC4648271 | biostudies-literature
Project description:Myeloperoxidase (MPO) is a target antigen for antineutrophil cytoplasmic autoantibodies (ANCA). There is evidence that MPO-ANCA cause necrotizing and crescentic glomerulonephritis (NCGN) and vasculitis. NCGN severity varies among patients with ANCA disease, and genetic factors influence disease severity. The role of genetics in MPO-ANCA NCGN severity was investigated using 13 inbred mouse strains, F1 and F2 hybrids, bone marrow chimeras, and neutrophil function assays. Mouse strains include founders of the Collaborative Cross. Intravenous injection of anti-MPO IgG induced glomerular crescents in >60% of glomeruli in 129S6/SvEv and CAST/EiJ mice, but <1% in A/J, DBA/1J, DBA/2J, NOD/LtJ, and PWK/PhJ mice. C57BL6J, 129S1/SvImJ, LP/J, WSB/EiJ, NZO/HILtJ, and C3H mice had intermediate severity. High-density genotypes at 542,190 single nucleotide polymorphisms were used to identify candidate loci for disease severity by identifying genomic regions that are different between 129S6/SvEv and 129S1/SvImJ mice, which are genetically similar but phenotypically distinct. C57BL/6 × 129S6 F2 mice were genotyped at 76 SNPs to capture quantitative trait loci for disease severity. The absence of a dominant quantitative trait locus suggests that differences in severity are the result of multiple gene interactions. In vivo studies using bone marrow chimeric mice and in vitro studies of neutrophil activation by anti-MPO IgG indicated that severity of NCGN is mediated by genetically determined differences in the function of neutrophils.
| S-EPMC3620395 | biostudies-literature
Project description:Although prominent personality theories postulate orthogonality between traits of positive emotionality (PEM) and negative emotionality (NEM), empirical evidence often demonstrates the opposite indicating a negative relationship. Therefore, it is not surprising that dopaminergic (DA) gene loci have been related to traits of positive and of NEM. The present genetic association study investigates the influence of two functional DA gene polymorphisms on Sadness as defined by the Affective Neuroscience Personality Scales (ANPS) in healthy Caucasians (n = 1041). We observed a significant interaction effect between the 10-repeat (10R) allele of the dopamine transporter (DAT1) gene and the methionine (Met) allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism (F((1,1018)) = 11.11; P < 0.001). Carriers of the 9R/9R and the Val/Val genotype showed dramatically reduced Sadness scores in comparison to the other three genotype configurations. Both the 9R/9R and the Val/Val genotypes characterized by reduced transporter density and high dopamine catabolism, respectively, have been separately related to personality traits of PEM and externalizing behavior in the past. The present findings indicate that gene variations of the DA system previously associated with PEM are at the same time protective against high NEM and can therefore constitute a resilience factor against depression.
| S-EPMC3236544 | biostudies-literature
Project description:BackgroundEpidemiological studies have shown inverse association between intelligence and coronary artery disease (CAD) risk, but the underlying mechanisms remain unclear.MethodsBased on 242 SNPs independently associated with intelligence, we calculated the genetic intelligence score (gIQ) for participants from 10 CAD case-control studies (n = 34,083) and UK Biobank (n = 427,306). From UK Biobank, we extracted phenotypes including body mass index (BMI), type 2 diabetes (T2D), smoking, hypertension, HDL cholesterol, LDL cholesterol, measured intelligence score, and education attainment. To estimate the effects of gIQ on CAD and its related risk factors, regression analyses was applied. Next, we studied the mediatory roles of measured intelligence and educational attainment. Lastly, Mendelian randomization was performed to validate the findings.ResultsIn CAD case-control studies, one standard deviation (SD) increase of gIQ was related to a 5% decrease of CAD risk (odds ratio [OR] of 0.95; 95% confidence interval [CI] 0.93 to 0.98; P = 4.93e-5), which was validated in UK Biobank (OR = 0.97; 95% CI 0.96 to 0.99; P = 6.4e-4). In UK Biobank, we also found significant inverse correlations between gIQ and risk factors of CAD including smoking, BMI, T2D, hypertension, and a positive correlation with HDL cholesterol. The association signals between gIQ and CAD as well as its risk factors got largely attenuated after the adjustment of measured intelligence and educational attainment. The causal role of intelligence in mediating CAD risk was confirmed by Mendelian randomization analyses.ConclusionGenetic components of intelligence affect measured intelligence and educational attainment, which subsequently affect the prevalence of CAD via a series of unfavorable risk factor profiles.
| S-EPMC7862508 | biostudies-literature
Project description:BackgroundSocioeconomic status (SES) is considered to be associated with the prevalence of Alzheimer's disease (AD). However, the causal association remain unclear. Here, we determining whether income has a causal protective effect on the risk of developing AD using Mendelian randomization (MR).MethodsSingle-nucleotide polymorphisms (SNPs) that are strongly associated with household income levels (P<5×10-8) from the UK Biobank (UKB) (n=286,301) were selected as instrumental variables for this study. Confounding instruments were removed through data set browsing. Selected SNPs were then harmonized with results from an AD genome-wide meta-analysis (71,880 cases, 383,378 controls) including both case-control and proxy cases. The analysis was conducted using MR methods, and multiple sensitivity analyses were applied for testing of potential bias.ResultsAfter confounding instrument removal and clumping, 9 SNPs associated with household income level identified by the UKB were left for the MR analysis. Our results demonstrated that higher household income level was causally related with a lower risk of AD (odds ratio 0.78, 95% confidence interval: 0.69-0.89; P<0.001). Multiple sensitivity analyses suggested no obvious evidence for heterogeneity or pleiotropy of the results.ConclusionsUnder MR assumptions, our results suggest robust evidence of a causal association between household income and AD risk, which may provide potential prevention strategies for this devastating disease.
| S-EPMC8421944 | biostudies-literature
Project description:BACKGROUND:Recent research has revealed that polymorphic behavioral strategies shape intra-and interspecific interactions and contribute to fitness in many animal species. A better understanding of the proximate mechanisms underlying these behavioral syndromes will enhance our grasp this phenomenon. Spiders in the genus Anelosimus exhibit inter-individual behavioral variation on several axes: individuals have consistent responses to stimuli (e.g. bold vs. shy individuals) and they are subsocial (exhibiting extended maternal care and sibling cooperation) across most of their range, but they sometimes form permanent social groups in northern temperate regions. Here, we seek genetic variants associated with boldness and with social structure in a socially polymorphic population of the spider Anelosimus studiosus. We also develop preliminary genomic resources, including a genome assembly and linkage map, that support this and future genomic research on this group. RESULTS:Remarkably, we identify a small genomic scaffold (~ 1200 bp) that harbors seven single nucleotide polymorphisms (SNPs) associated with boldness. Moreover, heterozygotes are less common than expected based on Hardy-Weinberg equilibrium, suggesting that either assortative mating or selection against heterozygotes may be occurring in this system. We find no loci significantly associated with social organization. Our draft genome assembly allows us to localize SNPs of interest in this study and to carry out genetic comparisons with other published genomes, although it remains highly fragmented. CONCLUSIONS:By identifying a locus associated with a well-studied animal personality trait, this study opens up avenues for future research to link behavioral studies of animal personality with genotype and fitness.
| S-EPMC6873478 | biostudies-literature
Project description:The dystrophin-glycoprotein complex and the alpha7beta1 integrin are trans-sarcolemmal linkage systems that connect and transduce contractile forces between muscle fibers and the extracellular matrix. alpha7beta1 is the major laminin binding integrin in skeletal muscle. Different functional variants of this integrin are generated by alternative splicing and post-translational modifications such as glycosylation and ADP-ribosylation. Here we report a species-specific difference in alpha7 chains that results from an intra-peptide proteolytic cleavage, by a serine protease, at the 603RRQ605 site. Site-directed mutagenesis of RRQ to GRQ prevents this cleavage. This RRQ sequence in the alpha7 integrin chain is highly conserved among vertebrates but it is absent in mice. Protein structure modeling indicates this cleavage site is located in an open region between the beta-propeller and thigh domains of the alpha7 chain. Compared with the non-cleavable alpha7 chain, the cleaved form enhances cell adhesion and spreading on laminin. Cleavage of the alpha7 chain is elevated upon myogenic differentiation, and this cleavage may be mediated by urokinase-type plasminogen activator. These results suggest proteolytic cleavage is a novel mechanism that regulates alpha7 integrin functions in skeletal muscle, and that the generation of such cleavage sites is another evolutionary mechanism for expanding and modifying protein functions.
| S-EPMC2602887 | biostudies-literature
Project description:Cancer metabolism has received renewed interest as a potential target for cancer therapy. In this study, we use a multi-scale modeling approach to interrogate the implications of three metabolic scenarios of potential clinical relevance: the Warburg effect, the reverse Warburg effect and glutamine addiction. At the intracellular level, we construct a network of central metabolism and perform flux balance analysis (FBA) to estimate metabolic fluxes; at the cellular level, we exploit this metabolic network to calculate parameters for a coarse-grained description of cellular growth kinetics; and at the multicellular level, we incorporate these kinetic schemes into the cellular automata of an agent-based model (ABM), iDynoMiCS. This ABM evaluates the reaction-diffusion of the metabolites, cellular division and motion over a simulation domain. Our multi-scale simulations suggest that the Warburg effect provides a growth advantage to the tumor cells under resource limitation. However, we identify a non-monotonic dependence of growth rate on the strength of glycolytic pathway. On the other hand, the reverse Warburg scenario provides an initial growth advantage in tumors that originate deeper in the tissue. The metabolic profile of stromal cells considered in this scenario allows more oxygen to reach the tumor cells in the deeper tissue and thus promotes tumor growth at earlier stages. Lastly, we suggest that glutamine addiction does not confer a selective advantage to tumor growth with glutamine acting as a carbon source in the tricarboxylic acid (TCA) cycle, any advantage of glutamine uptake must come through other pathways not included in our model (e.g., as a nitrogen donor). Our analysis illustrates the importance of accounting explicitly for spatial and temporal evolution of tumor microenvironment in the interpretation of metabolic scenarios and hence provides a basis for further studies, including evaluation of specific therapeutic strategies that target metabolism.
| S-EPMC6285468 | biostudies-literature