The mevalonate pathway is required for pyrimidine synthesis and survival of p53-deficient colon cancer cells in metabolically compromised environments
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PROVIDER: PRJNA510970 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we have investigated the effect of p53 deletion on the metabolic activity of colon cancer cells exposed to metabolic stress. In order to recreate the simultaneous reduction in oxygen and nutrient availability found in tumors, we cultured cancer cells as multicellular tumor spheroids. Under these conditions, p53 deficient cancer cells activate the expression of enzymes of the mevalonate pathway via the sterol regulatory element binding protein 2 (SREBP2). Moreover, inhibition of mevalonate pathway activity with statins selectively induced apoptosis in p53 deficient cancer cells exposed to metabolic stress. This effect was mediated by the requirement of p53 deficient cancer cells to synthesise ubiquinone (coenzyme Q10) to maintain TCA cycle activity, respiration and the production of pyrimidine nucleotides. Our study has revealed a novel link between isoprenoid synthesis by the mevalonate pathway and the electron transport function of ubiquinone, which is required for nucleotide biosynthesis. As a consequence, maintaining mevalonate pathway activity is essential for p53 deficient cancer cells to proliferate and survive under the metabolic constraints of the tumor microenvironment.
2019-11-15 | GSE124189 | GEO
Project description:Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase) or the critical downstream enzyme, DHODH (dihydroorotate dehydrogenase) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity. Higher expression of pyrimidine synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a novel therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
2019-04-09 | GSE129438 | GEO
Project description:Blocking pyrimidine de novo synthesis via inhibiting Dihydroorotate dehydrogenase (DHODH) is clinically used to treat autoimmunity and to prevent the growth of rapidly dividing cells including activated T-cells. We identified a previously unrecognized resistance of precursors of memory T-cells to pyrimidine starvation. While the treatment effectively blocks effector T-cells, numbers, function and transcriptional profiles of memory T-cells and their precursors remain completely unaltered. We pinpoint this effect to a narrow time-window in the early T-cell expansion phase, when developing effector, but not memory T-cells are selectively vulnerable to pyrimidine starvation. This stems from a higher proliferative pace of early effector T-cells paired with lower pyrimidine synthesis capacity compared to memory precursors. This differential sensitivity constitutes a novel, drug-targetable checkpoint that efficiently diminishes effector T-cells without harming the memory compartment. We envision that knowledge of this pyrimidine synthesis-based cell fate-determining particularity opens up new means to safely manipulate effector T-cell responses.
2023-01-10 | GSE200359 | GEO
Project description:Mevalonate metabolism is essential for proper functioning of eukaryotic cells. Widely prescribed drugs, like statins and bisphosphonates, inhibit specific enzymes in the mevalonate pathway and modulate immune responses. Intermediate metabolites of the pathway activate innate-like Vd2 T cells, while bisphosphonates effectively expand these cells for potential therapeutic use. Yet, the role of the mevalonate metabolism in Vd2 T cells is poorly defined. We show that in vitro and in vivo inhibition of the mevalonate metabolism results in compromised cytokine production and cytotoxic activity of Vd2 T cells. Impaired Vd2 T cell function is accompanied by global transcriptome changes. Protein prenylation and kinome analysis unraveled dysregulated signaling pathways as the leading cause of the reduced effector function of Vd2 T cells upon mevalonate pathway inhibition. Our findings reveal the importance of mevalonate metabolism for the proper functioning of Vd2 T cells and provides important considerations for improving their therapeutic use.
| EGAS00001007530 | EGA
Project description:Blocking pyrimidine de novo synthesis via inhibiting Dihydroorotate dehydrogenase (DHODH) is clinically used to treat autoimmunity and to prevent the growth of rapidly dividing cells including activated T-cells. We identified a previously unrecognized resistance of precursors of memory T-cells to pyrimidine starvation. While the treatment effectively blocks effector T-cells, numbers, function and transcriptional profiles of memory T-cells and their precursors remain completely unaltered. We pinpoint this effect to a narrow time-window in the early T-cell expansion phase, when developing effector, but not memory T-cells are selectively vulnerable to pyrimidine starvation. This stems from a higher proliferative pace of early effector T-cells paired with lower pyrimidine synthesis capacity compared to memory precursors. This differential sensitivity constitutes a novel, drug-targetable checkpoint that efficiently diminishes effector T-cells without harming the memory compartment. We envision that knowledge of this pyrimidine synthesis-based cell fate-determining particularity opens up new means to safely manipulate effector T-cell responses.
2023-01-10 | GSE200488 | GEO
Project description:Blocking pyrimidine de novo synthesis via inhibiting Dihydroorotate dehydrogenase (DHODH) is clinically used to treat autoimmunity and to prevent the growth of rapidly dividing cells including activated T-cells. We identified a previously unrecognized resistance of precursors of memory T-cells to pyrimidine starvation. While the treatment effectively blocks effector T-cells, numbers, function and transcriptional profiles of memory T-cells and their precursors remain completely unaltered. We pinpoint this effect to a narrow time-window in the early T-cell expansion phase, when developing effector, but not memory T-cells are selectively vulnerable to pyrimidine starvation. This stems from a higher proliferative pace of early effector T-cells paired with lower pyrimidine synthesis capacity compared to memory precursors. This differential sensitivity constitutes a novel, drug-targetable checkpoint that efficiently diminishes effector T-cells without harming the memory compartment. We envision that knowledge of this pyrimidine synthesis-based cell fate-determining particularity opens up new means to safely manipulate effector T-cell responses.
2023-01-10 | GSE200358 | GEO
Project description:Simvastatin has been widely used for treatment of hypercholesterolemia due to its ability to inhibit HMG-CoA reductase, the rate limiting enzyme of de novo cholesterol synthesis via mevalonate pathway. Its inhibitory action causes also depletion of pathway intermediates, farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP), which are inevitable for proper targeting of small GTPases (e.g. Ras proteins) to their site of action. We profiled by array the gene expression of MIA PaCa-2 cells treated with simvastatin, FPP, GGPP and their combinations. The inhibitory effect of statins on GFP-K-Ras protein trafficking were partially prevented by addition of the mevalonate pathway intermediates. We conclude that the anticancer effect of simvastatin is to a large extent mediated through isoprenoid intermediates of the mevalonate pathway.
2018-03-31 | E-MTAB-3263 | biostudies-arrayexpress
Project description:Isoprenoids are a class of ubiquitous organic molecules synthesized from the five-carbon starter unit isopentenyl pyrophosphate (IPP). Comprising more than 30,000 known natural products, isoprenoids serve various important biological functions in many organisms. In bacteria, undecaprenyl pyrophosphate is absolutely required for the formation of cell wall peptidoglycan and other cell surface structures, while ubiquinones and menaquinones, both containing an essential prenyl moiety, are key electron carriers in respiratory energy generation. There is scant knowledge on the nature and regulation of bacterial isoprenoid pathways. In order to explore the cellular responses to perturbations in the mevalonate pathway, responsible for producing the isoprenoid precursor IPP in many Gram-positive bacteria and eukaryotes, we constructed three strains of Staphylococcus aureus in which each of the mevalonate pathway genes is regulated by an IPTG inducible promoter. We used DNA microarrays to profile the transcriptional effects of downregulating the components of the mevalonate pathway in S. aureus and demonstrate that decreased expression of the mevalonate pathway leads to widespread downregulation of primary metabolism genes, an upregulation in virulence factors and cell wall biosynthetic determinants, and surprisingly little compensatory expression in other isoprenoid biosynthetic genes. We subsequently correlate these transcriptional changes with downstream metabolic consequences. We used microarrays to profile the transcriptional changes incurred when downregulating mvaS, mvaA, or mvaK in S. aureus. Keywords: stress response S. aureus mutants were generated in which mvaS, mvaA, or mvaK were placed under control of the IPTG-inducible Pspac promoter. These mutants, as well as wildtype RN4220 S. aureus, were grown with or without 1 mM IPTG, harvested in exponential phase, and their total RNA was extracted and hybridized to Affymetrix GeneChips. Experiments were done in triplicate.
2010-05-05 | E-GEOD-13424 | biostudies-arrayexpress
Project description:We have discovered that loss of wild-type p53 correlates with elevated expression of mevalonate pathway genes in murine liver cancer and in human tumors. Mechanistically p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene, which inhibits SREBP-2 maturation. In mice the increase in mevalonate gene expression occurs in premalignant p53-null hepatocytes at a stage when p53 is needed to actively suppress tumorigenesis. Either RNAi mediated suppression of key genes in the mevalonate pathway or pharmacological inhibition of its rate-limiting enzyme restricts the development of mouse hepatocellular carcinomas driven by p53 loss. Conversely, like p53 loss, ablation of ABCA1 promotes tumorigenesis in a murine model and is associated with increased SREBP-2 maturation. Our findings thereby demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated tumor suppression and outline the mechanism by which this occurs.
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Project description:Streptococcus pneumoniae is a Gram positive bacterium that causes severe invasive infection such as pneumonia, septicemia, meningitis and otitis media especially in children, the elderly and immune-compromised patients. Pneumococcal colonization and disease is often associated with biofilm formation. Bacteria in biofilms exhibit elevated resistance both to antibiotics and to host defense systems, which often results in persistent and difficult-to-treat infections. Therefore, the ongoing treat to human health posed by pneumococcal biofilms has prompted extensive research aimed to identify alternative targets and new antimicrobial agents that are effective against bacteria biofilms. The effective anti-biofilm strategies should include inhibition of microbial adhesion to the surface and of colonization, interference with the signal molecules modulating biofilm development and the disaggregation of the biofilm matrix. In this study, we examine the effect of DAM inhibitor small molecule pyrimidine-diones on streptococcus pneumoniae D-39 strain growth (planktonic and biofilm) and evaluate the changes in global gene expression using c-DNA microarray. The microarray analysis was performed on total RNA extracted from biofilms grown in 24-well microtiter plate with 7µm/ml pyrimidine-diones small molecule and control biofilms (biofilms grown without pyrimidine-diones small molecule). To validate the results of microarray, real-time RT-PCR was performed on 12 differentially expressed genes from six different functional groups. cDNA-microarray analysis detected a total of 259 genes that were significantly differentially expressed in biofilm growth with pyrimidine-diones small molecule. 204 genes were significantly down expressed and 55 genes were significantly up expressed in biofilms grown with 7µm/ml pyrimidine-diones small molecule. Among the 204 down expressed genes, 45 were hypothetical protein encoding gene and 159 were functional protein encoding genes. Of 55 up-regulated genes 21 were hypothetical genes and 34 were functional protein encoding genes. The functional annotation showed that gene involve in fatty acid metabolism, cell division, cell cycles, DNA metabolism, cell assembly were significantly down regulated and galactose metabolism related gene were up-expressed in biofilm grown with pyrimidine-diones small molecule.
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