Purine synthesis inhibitor L-Alanosine impairs mitochondrial function and stemness of brain tumor initiating cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE197728 | GEO | 2022/04/27
REPOSITORIES: GEO
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Project description:The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly. After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites. While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and post-translational mechanisms. One mRNA sample from each of Purine-Starved and Purine-Replete cells were analyzed using SL RNA-Seq methodology
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Project description:Genetic alterations that give rise to tumorigenesis result in altered epigenetic and gene expression profiles. We sought to identify and better understand potential consequences of MTAP deletion in glioblastoma by examining gene expression profiles of MTAP deleted and MTAP WT GBM cell lines. MTAP deletion results in accumulation of the abberant metabolite, MTA, with potential consequences to epigenetic regulation and signal transduction. We also examined the cellular response (gene expression) to purine deprivation with L-Alanosine treamment
2020-05-12 | GSE114867 | GEO
Project description:The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly. After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites. While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and post-translational mechanisms.
2014-02-01 | GSE48394 | GEO
Project description:Purine synthesis inhibitor L-Alanosine impairs mitochondrial function and stemness of brain tumor initiating cells
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Project description:To investigate whether BRD4-chromatin binding is modulated by purine levels, we performed BRD4 ChIP-seq in cells with SLC nucleoside transporters knockout, or cells with de novo purine synthesis inhibitor 6-MP treatment. (+)-JQ1, an inhibitor which disrupts BRD4 and acetylated histone binding, was used as a positive control.
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2023-10-04 | GSE186319 | GEO
Project description:Glioblastoma (GBM) cells’ stemness-like features and lineage plasticity promote tumor progression. Here, we demonstrate that Clemastine, a drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary GBM cultures bearing PDGFRA amplification. We show that these effects of GBM cells were accompanied by altered gene expression profiling indicative of a more differentiated state of tumor cells, in resonating with Clemastine’s activity in promoting the differentiation of normal oligodendrocyte progenitors (OPCs) into mature oligodendrocyte. Functional assays for proteins that can be pharmacologically targeted by Clemastine, including histamine receptors, muscarinic receptors, and Emopamil binding protein (EBP), revealed the essential roles of these proteins in sustaining GBM cell propagation and suggested that Clemastine likely impairs tumor cells via targeting multiple pathways. Finally, we showed that a PDGFB-driven mouse glioma model, representing the proneural subtype GBMs, was similarly susceptible to Clemastine treatment. Collectively, these results identify pathways that are essential for maintaining the proneural progenitor features of GBMs, and suggest that non-oncology, low toxicity drugs with OPC differentiation promoting effects, such as Clemastine, can be exploited for targeting GBM cell’s progenitor property.
2023-10-04 | GSE186392 | GEO
Project description:Cell cycle and metabolism are two major outputs controlled by circadian rhythm in many organisms. Here we show that the three processes were linked through inosine 5'-phosphate dehydrogenase (impdh), a rate-limiting enzyme in de novo purine synthesis. We using adult zebrafish as a model system,we applied a genome-wide transcriptome approach that allowed us to investigate circadian gene expression. The whole-genome transcriptome profiles of adult brain in time-series were assayed on Agilent zebrafish microarrays. We used a similar statistical method to identify zebrafish circadian genes (ZCOG) as our previous study in larval zebrafish. Three isoforms of impdh show strong circadian oscillations in different tissues of zebrafish. impdh1a contributes to the ocular development and pigment synthesis, impdh2 promotes and impdh1b delays the development. By limiting the GTP required by DNA synthesis, impdh2 contributes to the daily rhythm of S phase in cell cycle. Multiple enzymes in the de novo purine synthesis pathway show the same circadian oscillations with peaks similar to impdh2. The circadian expression of this pathway is conserved in mouse liver. In summary, we show that the circadian regulation of de novo purine synthesis that supplies crucial building blocks for DNA replication is critical for gating cell cycle in circadian rhythm. Adult zebrafish were sacrificed and dissected at 4h intervals starting at CT0 in both LD and DD conditions for 12 time points. Total RNA of individual zebrafish brain was extracted using Trizol (Invitrogen, Carlsbad, CA) according to the manufacturerM-bM-^@M-^Ys instruction. Microarrays were manufactured by Agilent Technologies (Agilent Technologies, Palo Alto, CA), containing 43,603 probes for zebrafish whole-genome transcriptional profiling.
2013-10-01 | E-GEOD-51277 | biostudies-arrayexpress
Project description:Cell cycle and metabolism are two major outputs controlled by circadian rhythm in many organisms. Here we show that the three processes were linked through inosine 5'-phosphate dehydrogenase (impdh), a rate-limiting enzyme in de novo purine synthesis. We using adult zebrafish as a model system,we applied a genome-wide transcriptome approach that allowed us to investigate circadian gene expression. The whole-genome transcriptome profiles of adult brain in time-series were assayed on Agilent zebrafish microarrays. We used a similar statistical method to identify zebrafish circadian genes (ZCOG) as our previous study in larval zebrafish. Three isoforms of impdh show strong circadian oscillations in different tissues of zebrafish. impdh1a contributes to the ocular development and pigment synthesis, impdh2 promotes and impdh1b delays the development. By limiting the GTP required by DNA synthesis, impdh2 contributes to the daily rhythm of S phase in cell cycle. Multiple enzymes in the de novo purine synthesis pathway show the same circadian oscillations with peaks similar to impdh2. The circadian expression of this pathway is conserved in mouse liver. In summary, we show that the circadian regulation of de novo purine synthesis that supplies crucial building blocks for DNA replication is critical for gating cell cycle in circadian rhythm.
2013-10-01 | GSE51277 | GEO
Project description:Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor, and surgical resection is a key part of the standard-of-care. In fluorescence-guided surgery (FGS), fluorophores are used to differentiate tumor tissue from surrounding normal brain. The heme synthesis pathway converts 5-aminolevulinic acid (5-ALA), a fluorogenic substrate, to the fluorophore protoporphyrin IX (PpIX). The resulting fluorescence is thought to be specific to transformed glioma cells, but this specificity has not been examined at single cell level. Here, we performed paired single cell imaging and RNA sequencing of individual cells (SCOPE-seq2) on human GBM surgical specimens with visible PpIX fluorescence from patients who received 5-ALA prior to surgery. SCOPE-seq2 allows us to simultaneously measure PpIX fluorescence by imaging and unambiguously identify transformed glioma cells from single-cell RNA-seq (scRNA-seq). We observed that 5-ALA treatment results in labeling that is not specific to transformed tumor cells. In cell culture experiments, we further demonstrated untransformed cells can be labeled by 5-ALA directly or by PpIX secreted from surrounding transformed cells. In acute slice cultures from mouse glioma models, we showed that 5-ALA preferably labels GBM tumor tissue over non-neoplastic brain tissue at bulk level, and that this contrast is not due to blood-brain-barrier disruption. Taken together, our findings support the use of 5-ALA as an indicator of GBM tissue, but not as a specific marker of transformed glioma cells.
2022-11-30 | GSE218331 | GEO