DHODH modulates immune evasion of cancer cells via CDP-Choline dependent phospholipid metabolism
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE243486 | GEO | 2025/03/12
REPOSITORIES: GEO
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Project description:DHODH modulates immune evasion of cancer cells via CDP-Choline dependent phospholipid metabolism
| PRJNA1018578 | ENA
Project description:The mitochondrial respiratory chain assembles into higher order complexes termed supercomplexes (SCs) under certain physiological or metabolic stimuli. A small molecule screen developed by the lab identified DHODH inhibitors as potent activators of SC assembly in cancer cells. To investigate the proteomic regulation of SCs under nucleotide deficiency, we treated U2OS cells for 48 hours with Brequinar (500 nM). Proteomic analysis highlighted strong signatures of respiratory chain subunit abundance and peroxisomal-derived ether phospholipid synthesis enzymes. Bypassing DHODH inhibition through uridine supplementation prevented these alterations. These findings establish a coordinated cellular response to reduced nucleotide pools that stimulates ether phospholipid synthesis and respiratory chain supra-assembly.
2022-02-16 | PXD023882 | Pride
Project description:Sen2013 - Phospholipid Synthesis in P.knowlesi
The model describes the multiple phospholipid synthetic pathways in Plasmodium knowlesi.
This model is described in the article:
Kinetic modelling of phospholipid synthesis in Plasmodium knowlesi unravels crucial steps and relative importance of multiple pathways.
Sen P, Vial HJ, Radulescu O.
BMC Syst Biol 2013 Nov; 7(1): 123
Abstract:
BACKGROUND: Plasmodium is the causal parasite of malaria, infectious disease responsible for the death of up to one million people each year. Glycerophospholipid and consequently membrane biosynthesis are essential for the survival of the parasite and are targeted by a new class of antimalarial drugs developed in our lab. In order to understand the highly redundant phospholipid synthethic pathways and eventual mechanism of resistance to various drugs, an organism specific kinetic model of these metabolic pathways need to be developed in Plasmodium species. RESULTS: Fluxomic data were used to build a quantitative kinetic model of glycerophospholipid pathways in Plasmodium knowlesi. In vitro incorporation dynamics of phospholipids unravels multiple synthetic pathways. A detailed metabolic network with values of the kinetic parameters (maximum rates and Michaelis constants) has been built. In order to obtain a global search in the parameter space, we have designed a hybrid, discrete and continuous, optimization method. Discrete parameters were used to sample the cone of admissible fluxes, whereas the continuous Michaelis and maximum rates constants were obtained by local minimization of an objective function.The model was used to predict the distribution of fluxes within the network of various metabolic precursors.The quantitative analysis was used to understand eventual links between different pathways. The major source of phosphatidylcholine (PC) is the CDP-choline Kennedy pathway.In silico knock-out experiments showed comparable importance of phosphoethanolamine-N-methyltransferase (PMT) and phosphatidylethanolamine-N-methyltransferase (PEMT) for PC synthesis.The flux values indicate that, major part of serine derived phosphatidylethanolamine (PE) is formed via serine decarboxylation, whereas major part of phosphatidylserine (PS) is formed by base-exchange reactions.Sensitivity analysis of CDP-choline pathway shows that the carrier-mediated choline entry into the parasite and the phosphocholine cytidylyltransferase reaction have the largest sensitivity coefficients in this pathway, but does not distinguish a reaction as an unique rate-limiting step.
CONCLUSION: We provide a fully parametrized kinetic model for the multiple phospholipid synthetic pathways in P. knowlesi. This model has been used to clarify the relative importance of the various reactions in these metabolic pathways. Future work extensions of this modelling strategy will serve to elucidate the regulatory mechanisms governing the development of Plasmodium during its blood stages, as well as the mechanisms of action of drugs on membrane biosynthetic pathways and eventual mechanisms of resistance.
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2024-09-02 | BIOMD0000000495 | BioModels
Project description:Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multi-omic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. We combined metabolomics, CRISPR screening and transcriptomic data across >700 solid tumor cell lines and identified dihydroorotate dehydrogenase (DHODH), a critical enzyme in pyrimidine synthesis, as a potential treatment target. Of note, DHODH inhibition is currently under clinical investigation in patients with hematologic malignancies. In neuroblastoma, DHODH expression was identified as an independent risk factor for aggressive disease, and high DHODH levels correlated to worse overall and event-free survival. A subset of tumors with the highest DHODH expression was associated with a dismal prognosis, with a 5-year survival of <10%. In xenograft and transgenic neuroblastoma mouse models treated with the DHODH inhibitor brequinar, tumor growth was dramatically reduced, and survival was extended. Furthermore, brequinar treatment was shown to reduce the expression of MYC targets in three different neuroblastoma models in vivo. A combination of brequinar and temozolomide was curative in the majority of transgenic TH-MYCN neuroblastoma mice, indicating a highly active clinical combination therapy. Overall, DHODH inhibition combined with temozolomide has therapeutic potential in neuroblastoma and we propose this combination for clinical testing.
2022-07-27 | GSE209811 | GEO
Project description:Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multi-omic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. We combined metabolomics, CRISPR screening and transcriptomic data across >700 solid tumor cell lines and identified dihydroorotate dehydrogenase (DHODH), a critical enzyme in pyrimidine synthesis, as a potential treatment target. Of note, DHODH inhibition is currently under clinical investigation in patients with hematologic malignancies. In neuroblastoma, DHODH expression was identified as an independent risk factor for aggressive disease, and high DHODH levels correlated to worse overall and event-free survival. A subset of tumors with the highest DHODH expression was associated with a dismal prognosis, with a 5-year survival of <10%. In xenograft and transgenic neuroblastoma mouse models treated with the DHODH inhibitor brequinar, tumor growth was dramatically reduced, and survival was extended. Furthermore, brequinar treatment was shown to reduce the expression of MYC targets in three different neuroblastoma models in vivo. A combination of brequinar and temozolomide was curative in the majority of transgenic TH-MYCN neuroblastoma mice, indicating a highly active clinical combination therapy. Overall, DHODH inhibition combined with temozolomide has therapeutic potential in neuroblastoma and we propose this combination for clinical testing.
2022-07-27 | GSE209812 | GEO
Project description:We have previously observed protein level changes after treating human cells with two novel inhibitors of the enzyme DHODH. This study was designed to study up to what degree these protein differences can be also observed at level of mRNA. As part of the de novo pyrimidine synthesis pathway, DHODH inhibition is expected to decrease the levels of total RNA in cells. However, some effector proteins associated with the p53 pathway are increased after treatment with these inhibitors. This study aims to answer if the observed protein differences are based on an increased transcription or due to protein stabilization.
2018-03-21 | GSE87577 | GEO
Project description:Metabolic reprogramming has emerged as key regulators of cell fate decisions. Whereas the glucose and amino acid metabolism have been extensively documented, the roles of lipid metabolism in pluripotency remain largely unexplored. Here, we report that the CDP-Ethanolamine (CDP-Etn) pathway for phosphatidylethanolamine synthesis is required for somatic cell reprogramming at the early stage. Mechanistically, the CDP-Etn pathway inhibits NF-κB signaling and mesenchymal genes in a Pebp1 dependent manner, resulting in accelerated mesenchymal-to-epithelial transition and enhanced reprogramming. In addition, we show that phospholipids are critical for the growth of mESC though without effects on pluripotency. Our study reveals an unforeseen connection between phospholipids, cell migration and pluripotency and highlights the importance of phospholipids in cell fate transitions.
2019-08-25 | GSE116080 | GEO
Project description:Children with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. Multiple lines of evidence point towards the enzyme dihydroorotate dehydrogenase (DHODH) as a metabolic vulnerability in dysregulated and malignant T‑cells. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis (e.g., uridine, cytidine). Therefore, inhibiting DHODH via small molecule inhibitors (DHODHi) rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and ultimately death. T‑lymphoblasts appear to be specifically and exquisitely sensitive to nucleotide starvation following DHODHi. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T‑ALL. Additionally, we have identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODHi. Through a series of metabolic assays, we show that leukemia cells, in the setting of nucleotide starvation, have changes in their mitochondrial membrane potential and may be more highly dependent on alternative fuel sources. We hope these changes point to a metabolic vulnerability that may distinguish them from normal T-cells and other normal hematopoietic cells and offer an exploitable therapeutic opportunity. The availability of clinical-grade DHODH inhibitors currently in human clinical trials speaks to the potential for rapidly advancing this work into the clinic.
2023-12-07 | GSE216753 | GEO
Project description:Neuroblastoma is an embryonal tumor which originates from neural crest progenitor cells that fail to differentiate along their predefined route to sympathetic neurons or sympatho-adrenergic adrenal cells. It is the most common extracranial tumor of childhood and accounts for 15% of all childhood cancer deaths. Especially patients suffering from high grade or relapsed neuroblastoma have poor outcome in spite of aggressive treatment regimens including autologous stem cell transplantation. Those patients are in urgent need of additional effective therapies which demands the development of targeted approaches. Dihydroorotatedehydrogenase (DHODH) is the fourth enzyme of the pyrimidine synthesis pathway which oxidizes dihydroorotate to orotate. In recent past it became a potential drug target for cancer treatment because of its keyrole in processing essential pyrimidine nucleotides. On the basis of the existing data, functional inhibition of DHODH is considered to be promising therapeutic option for several tumor entities like advanced colorectal, breast or lung-cancers. Leflunomide is an established drug in treatment of the autoimmune diseases rheumatoid arthritis and multiple sclerosis. In the liver Leflunomide becomes converted to its active metabolite called Teriflunomide, which inhibits the activity of DHODH directly. In recent times Leflunomide is also used for therapy against the Cytomegalovirus and the BK virus. Also for Melanoma was shown recently a decreased growth rate due to Leflunomide treatment in a zebrafish and a mouse model. As Melanoma is a malignant tumor of the skin, which derives also from neural crest progenitor cells, a coherent investigation of effictivity of Leflunomide in neuroblastoma celllines showed first promising results. The aim of our study was to reanalyse the effectivity of Leflunomide in Neuroblastoma and to shed further light in its biological mode of action. Three+B52 biological samples of the human neuroblastoma cell line IMR32 were treated with DMSO or Teriflunomide [118 ￂﾵM]
2015-03-27 | E-GEOD-67338 | biostudies-arrayexpress
Project description:Neuroblastoma is an embryonal tumor which originates from neural crest progenitor cells that fail to differentiate along their predefined route to sympathetic neurons or sympatho-adrenergic adrenal cells. It is the most common extracranial tumor of childhood and accounts for 15% of all childhood cancer deaths. Especially patients suffering from high grade or relapsed neuroblastoma have poor outcome in spite of aggressive treatment regimens including autologous stem cell transplantation. Those patients are in urgent need of additional effective therapies which demands the development of targeted approaches. Dihydroorotatedehydrogenase (DHODH) is the fourth enzyme of the pyrimidine synthesis pathway which oxidizes dihydroorotate to orotate. In recent past it became a potential drug target for cancer treatment because of its keyrole in processing essential pyrimidine nucleotides. On the basis of the existing data, functional inhibition of DHODH is considered to be promising therapeutic option for several tumor entities like advanced colorectal, breast or lung-cancers. Leflunomide is an established drug in treatment of the autoimmune diseases rheumatoid arthritis and multiple sclerosis. In the liver Leflunomide becomes converted to its active metabolite called Teriflunomide, which inhibits the activity of DHODH directly. In recent times Leflunomide is also used for therapy against the Cytomegalovirus and the BK virus. Also for Melanoma was shown recently a decreased growth rate due to Leflunomide treatment in a zebrafish and a mouse model. As Melanoma is a malignant tumor of the skin, which derives also from neural crest progenitor cells, a coherent investigation of effictivity of Leflunomide in neuroblastoma celllines showed first promising results. The aim of our study was to reanalyse the effectivity of Leflunomide in Neuroblastoma and to shed further light in its biological mode of action.
2015-03-27 | GSE67338 | GEO