GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress

Cancer Discovery, Год журнала: 2023, Номер 14(1), С. 158 - 175

Опубликована: Окт. 30, 2023

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links to and has significant therapeutic implications. GTP, but not other nucleotides, the activity of Rac1, guanine nucleotide-binding protein, which promotes dephosphorylation serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, previously known activate repair, nonhomologous end joining. In patients mouse models glioblastoma, Rac1 dephosphorylated Abi-1 mediate resistance standard-of-care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 axis limited brain cancer, as GTP supplementation Abi-1-S323 in nonmalignant cells protects tissues from insult. This unexpected ability regulate independently deoxynucleotide pools important implications for normal physiology cancer treatment. A newly described GTP-dependent an link between nucleotide repair. Disrupting this pathway can overcome therapy while augmenting it mitigate injury tissues. article featured Selected Articles Issue, p. 5.

Язык: Английский

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Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma

Cancer & Metabolism, Год журнала: 2024, Номер 12(1)

Опубликована: Апрель 9, 2024

Abstract Background Diffuse midline gliomas (DMG), including diffuse intrinsic pontine (DIPGs), are a fatal form of brain cancer. These tumors often carry driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M characterized by altered metabolism and resistance standard care radiation (RT) but how the H3K27M mediates metabolic response consequent treatment is uncertain. Methods We performed metabolomics irradiated untreated isogenic DMG cell lines observed an H3K27M-specific enrichment for purine synthesis pathways. profiled expression enzymes in publicly available patient data our models, quantified using stable isotope tracing, vitro vivo de novo salvage inhibition combination with RT. Results cells activate fashion. In absence genotoxic treatment, H3K27M-expressing have higher relative activity apparent lower demonstrated via tracing key metabolites hypoxanthine-guanine phosphoribosyltransferase (HGPRT), rate-limiting enzyme into IMP GMP. Inhibition guanylate radiosensitized . Irradiated upregulated HGPRT hypoxanthine-derived maintained high levels guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization treated RT inhibition. Silencing combined markedly suppressed tumor growth Conclusions Our results indicate that rely highly active synthesis, both from However, free bases mature guanylates can bypass synthetic pathway. conclude inhibiting may be promising strategy overcome tumors.

Язык: Английский

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ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer

Cancer Letters, Год журнала: 2022, Номер 552, С. 215981 - 215981

Опубликована: Окт. 27, 2022

Язык: Английский

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Metabolomic and Lipidomic Profiling of Gliomas—A New Direction in Personalized Therapies

Cancers, Год журнала: 2022, Номер 14(20), С. 5041 - 5041

Опубликована: Окт. 14, 2022

In addition to being the most common primary brain tumor, gliomas are also among difficult diagnose and treat. At present, “gold standard” in glioma treatment entails surgical resection of largest possible portion followed by temozolomide therapy radiation. However, this approach does not always yield desired results. Additionally, ability cross blood-brain barrier remains a major challenge for new potential drugs. Thus, researchers continue search targeted therapies that can be individualized based on specific characteristics each case. Metabolic lipidomic research may represent two best ways achieve goal, as they enable detailed insights into changes profile small molecules biological system/specimen. This article reviews approaches analysis alterations biochemical pathways, it provides an overview clinical results support personalized future.

Язык: Английский

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Chemical QuantArray: A Quantitative Tool for Mass Spectrometry Imaging

Analytical Chemistry, Год журнала: 2023, Номер 95(30), С. 11243 - 11253

Опубликована: Июль 20, 2023

Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) is a powerful analytical technique that provides spatially preserved detection and quantification of analytes in tissue specimens. However, clinical translation still requires improved throughput, precision, accuracy. To accomplish this, we created "Chemical QuantArray", gelatin microarray (TMA) mold filled with serial dilutions isotopically labeled endogenous metabolite standards. The then cryo-sectioned onto homogenate to produce calibration curves. improve precision accuracy, automatically remove pixels outside each TMA well investigated several intensity normalizations, including the utilization second stable isotope internal standard (IS). Chemical QuantArray enables metabolites over wide dynamic range significantly current approaches. reduces space needed on MALDI slides for standards by approximately 80%. Furthermore, removal empty normalization an or matrix peak provided (<20% RSD) accuracy DEV). Finally, demonstrate applicability quantifying multiple purine 14 tumor specimens using single slide. improves characteristics practical feasibility MALDI-MSI translational applications.

Язык: Английский

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Treatment of IDH-mutant glioma in the INDIGO era

npj Precision Oncology, Год журнала: 2024, Номер 8(1)

Опубликована: Июль 18, 2024

Gliomas are the most common primary brain tumor and uniformly lethal. Despite significant advancements in understanding genetic landscape of gliomas, standard-of-care has remained largely unchanged. Subsets gliomas defined by gain-of-function mutations metabolic genes encoding isocitrate dehydrogenase (IDH). Efforts to exploit mutant IDH activity and/or directly inhibit it with inhibitors have been focus over a decade research. The recently published INDIGO trial, demonstrating benefit inhibitor vorasidenib patients low-grade IDH-mutant introduces new era precision medicine tumors that is poised change standard-of-care. In this review, we highlight contextualize results trial introduce key questions whose answers will guide how may be used clinic. We discuss possible combination therapies inhibition future directions for clinical translational

Язык: Английский

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Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 17, 2024

H3K27M diffuse midline gliomas (DMG), including intrinsic pontine (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like AC-like phenotypes perform transcriptomics, metabolomics, bioenergetic profiling to identify metabolic programs the different states. We then define strategies target vulnerabilities within specific tumor populations. show a mesenchymal phenotype are sensitized ferroptotic cell death. In contrast, OPC-like upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), accordingly sensitive statins OXPHOS inhibitors. Additionally, inhibitors efficacy extend survival preclinical orthotopic established with stem-like DMG Together, this study demonstrates subtypes DMGs harbor distinct can be uniquely selectively targeted for therapeutic gain.

Язык: Английский

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Proteomic profiling of gliomas unveils immune and metabolism-driven subtypes with implications for anti-nucleotide metabolism therapy

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Ноя. 19, 2024

Gliomas exhibit high heterogeneity and poor prognosis. Despite substantial progress has been made at the genomic transcriptomic levels, comprehensive proteomic characterization its implications remain largely unexplored. In this study, we perform profiling of gliomas using 343 formalin-fixed paraffin-embedded tumor samples 53 normal-appearing brain from 188 patients, integrating these data with panel information clinical outcomes. The analysis uncovers two distinct subgroups: Subgroup 1, metabolic neural subgroup, enriched in enzymes neurotransmitter receptor proteins, 2, immune marked by upregulation inflammatory proteins. These subgroups show significant differences prognosis, tumorigenesis, microenvironment dysregulation, potential therapeutics, highlighting critical roles processes glioma biology patient Through a detailed investigation pathways guided our findings, dihydropyrimidine dehydrogenase (DPYD) thymidine phosphorylase (TYMP) emerge as prognostic biomarkers linked to reprogramming nucleotide metabolism. Functional validation patient-derived stem cells animal models highlights metabolism promising therapy target for gliomas. This integrated multi-omics introduces classification identifies DPYD TYMP key biomarkers, offering insights into pathogenesis treatment strategies. Comprehensive molecular characterisations could shed light on prognosis Here, authors revealing neuron-related well

Язык: Английский

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Non-oncogene dependencies: Novel opportunities for cancer therapy

Biochemical Pharmacology, Год журнала: 2024, Номер 228, С. 116254 - 116254

Опубликована: Май 3, 2024

Язык: Английский

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Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma

iScience, Год журнала: 2025, Номер 28(2), С. 111769 - 111769

Опубликована: Янв. 8, 2025

Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug have been proposed where more plastic metabolic response can play role. Here, we show that upon resistance, glioblastoma (GBM) cells increased oxidative stress, mitochondria function, protein aggregation. Gamma (γ)-glutamylcyclotranserase (GGCT), an enzyme in the γ-glutamyl cycle for glutathione production, located on chromosome 7 which commonly amplified GBM also resistance. We further observe byproduct GGCT-pyroglutamic acid-can bind aggregating proteins genetic pharmacological inhibition GGCT prevents Finally, found aggregation, expression, pyroglutamic acid staining recurrent patient samples, adjacent non-tumor brain, Alzheimer's brains. These findings suggest new pathway aggregation within resistant brain should be studied other disorders.

Язык: Английский

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