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Purine synthesis inhibitor L-Alanosine impairs mitochondrial function and stemness of brain tumor initiating cells

ABSTRACT: Purine synthesis inhibitor L-Alanosine impairs mitochondrial function and stemness of brain tumor initiating cells

PROVIDER: PRJNA811644 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18186751_1.fastq.gz	Fastqsanger.gz
	SRR18186751_2.fastq.gz	Fastqsanger.gz
	SRR18186752_1.fastq.gz	Fastqsanger.gz
	SRR18186752_2.fastq.gz	Fastqsanger.gz
	SRR18186753_1.fastq.gz	Fastqsanger.gz

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Purine synthesis inhibitor L-Alanosine impairs mitochondrial function and stemness of brain tumor initiating cells

2022-04-27 | GSE197728 | GEO

Purine Synthesis Inhibitor L-Alanosine Impairs Mitochondrial Function and Stemness of Brain Tumor Initiating Cells.

Project description:Glioblastoma (GBM) is a lethal brain cancer exhibiting high levels of drug resistance, a feature partially imparted by tumor cell stemness. Recent work shows that homozygous MTAP deletion, a genetic alteration occurring in about half of all GBMs, promotes stemness in GBM cells. Exploiting MTAP loss-conferred deficiency in purine salvage, we demonstrate that purine blockade via treatment with L-Alanosine (ALA), an inhibitor of de novo purine synthesis, attenuates stemness of MTAP-deficient GBM cells. This ALA-induced reduction in stemness is mediated in part by compromised mitochondrial function, highlighted by ALA-induced elimination of mitochondrial spare respiratory capacity. Notably, these effects of ALA are apparent even when the treatment was transient and with a low dose. Finally, in agreement with diminished stemness and compromised mitochondrial function, we show that ALA sensitizes GBM cells to temozolomide (TMZ) in vitro and in an orthotopic GBM model. Collectively, these results identify purine supply as an essential component in maintaining mitochondrial function in GBM cells and highlight a critical role of mitochondrial function in sustaining GBM stemness. We propose that purine synthesis inhibition can be beneficial in combination with the standard of care for MTAP-deficient GBMs, and that it may be feasible to achieve this benefit without inflicting major toxicity.

| S-EPMC9025092 | biostudies-literature

Transcriptomic effects of purine metabolism inhibition and nucleolus rRNA synthesis disruption on murine acute myeloid leukemia stem cell

Project description:Through targeted metabolomics analysis of bulk leukemia cells and leukemia stem cells (LSCs) derived from the MLL-AF9-driven acute myeloid leukemia (AML) model, in comparison with normal granulocyte-monocyte progenitor (GMP) cells and whole bone marrow (WBM) cells from normal mice, we identified enhanced purine metabolism in AML LSCs. Pharmacological targeting of the purine metabolism using mycophenolate mofetil (MMF) resulted in decreased levels of purine metabolites crucial for nucleolus rRNA synthesis. Importantly, inhibition of purine metabolism or disruption of the nucleolus rRNA synthesis, achieved by inhibiting pol I activity with CX-5461, triggered myeloid differentiation in the MLL-AF9-driven AML LSCs. These findings unveil a regulatory axis involving purine metabolism and nucleolar rRNA synthesis in maintaining AML LSC activity.

2025-02-17 | GSE263345 | GEO

De Novo Purine Synthesis Mediates Circadian Control of Cell Cycle in Zebrafish (array)

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

De Novo Purine Synthesis Mediates Circadian Control of Cell Cycle in Zebrafish (array)

2013-10-01 | GSE51277 | GEO

Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis

Project description:Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines, and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, AICAR, followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the SHMT1/2 inhibitor - SHIN1, and by AICAR supplementation. Mechanistically, the metabolically-driven differentiation is independent of nucleotide sensing through mTORC1 and AMPK, and is instead mediated by protein kinase C (PKC). Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate-deficiency induced anemia.

2024-02-07 | GSE245011 | GEO

Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis

Project description:Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis

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The nucleotide messenger (p)ppGpp is an anti-inducer of the purine synthesis transcription regulator PurR in Bacillus

Project description:The nucleotide messenger (p)ppGpp allows bacteria to adapt to fluctuating environments by reprogramming the transcriptome. Despite its well-recognized role in gene regulation, (p)ppGpp is only known to directly affect transcription in Proteobacteria by binding to the RNA polymerase. Here we reveal a different mechanism of gene regulation by (p)ppGpp in Firmicutes from soil bacteria to pathogens: (p)ppGpp directly binds to the transcription factor PurR to downregulate purine biosynthesis. We identified PurR as a receptor of (p)ppGpp in Bacillus anthracis and revealed that (p)ppGpp strongly enhances PurR binding to its regulon in the Bacillus subtilis genome. A co-structure reveals that (p)ppGpp binds to a PurR pocket reminiscent of the active site of PRT enzymes that has been repurposed to serve a purely regulatory role, where the effectors (p)ppGpp and PRPP compete to allosterically control transcription. PRPP inhibits PurR DNA binding to induce transcription of purine synthesis genes, whereas (p)ppGpp antagonizes PRPP to enhance PurR DNA binding and repress transcription. A (p)ppGpp-refractory purR mutant fails to downregulate purine synthesis genes upon starvation. Our work establishes the precedent of (p)ppGpp as a classical effector of transcription repressors and reveals the key function of (p)ppGpp in regulating nucleotide synthesis through gene regulation, from the human intestinal tract to host-pathogen interfaces.

2021-12-10 | GSE185164 | GEO

Chromatin remodeling factor BRG1 regulates stemness and chemosensitivity of glioma initiating cells

Project description:Chromatin remodeling factor BRG1 regulates stemness and chemosensitivity of glioma initiating cells

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Class 3 PI3K coactivates the circadian clock to promote rhythmic de novo purine synthesis

Project description:Class 3 PI3K coactivates the circadian clock to promote rhythmic de novo purine synthesis

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