Background Levels of Neomorphic 2-hydroxyglutarate Facilitate Proliferation of Primary Fibroblasts

Dvořák, Aleš; Zelenka, Jaroslav; Smolková, Katarína; Vı́tek, Libor; Ježek, Petr

doi:10.33549/physiolres.933249

Cited by 12 publications

(8 citation statements)

References 45 publications

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“…The analytes were derivatized with pyridine/N,O-bis(trimethylsilyl)acetamide/chlorotrimethylsilane (8:4:2, v/v/v) at 65°C for 75 min. Derivatized samples were injected directly into a gas chromatograph -mass spectrometer (GC-MS, GC 6890N, MD 5973, Agilent Technologies, CA, United States) (Dvorak et al, 2017). The analyte amount was normalized to the IS and the cell count and calculated as a % of the control.…”

Section: Gc-ms Analysis Of Intracellular Metabolites Of the Tricarboxmentioning

confidence: 99%

The Effects of Bilirubin and Lumirubin on Metabolic and Oxidative Stress Markers

et al. 2021

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For severe unconjugated hyperbilirubinemia the gold standard treatment is phototherapy with blue-green light, producing more polar photo-oxidation products, believed to be non-toxic. The aim of the present study was to compare the effects of bilirubin (BR) and lumirubin (LR), the major BR photo-oxidation product, on metabolic and oxidative stress markers. The biological activities of these pigments were investigated on several human and murine cell lines, with the focus on mitochondrial respiration, substrate metabolism, reactive oxygen species production, and the overall effects on cell viability. Compared to BR, LR was found to be much less toxic, while still maintaining a similar antioxidant capacity in the serum as well as suppressing activity leading to mitochondrial superoxide production. Nevertheless, due to its lower lipophilicity, LR was less efficient in preventing lipoperoxidation. The cytotoxicity of BR was affected by the cellular glycolytic reserve, most compromised in human hepatoblastoma HepG2 cells. The observed effects were correlated with changes in the production of tricarboxylic acid cycle metabolites. Both BR and LR modulated expression of PPARα downstream effectors involved in lipid and glucose metabolism. Proinflammatory effects of BR, evidenced by increased expression of TNFα upon exposure to bacterial lipopolysaccharide, were observed in murine macrophage-like RAW 264.7 cells. Collectively, these data point to the biological effects of BR and its photo-oxidation products, which might have clinical relevance in phototherapy-treated hyperbilirubinemic neonates and adult patients.

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Section: Gc-ms Analysis Of Intracellular Metabolites Of the Tricarboxmentioning

confidence: 99%

The Effects of Bilirubin and Lumirubin on Metabolic and Oxidative Stress Markers

et al. 2021

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“…LC-MS-based metabolomic profiling showed that 2R-HG levels in AML cells harboring the IDH1 R132 mutation and in serum from these patients was ~50-fold higher than in WT AML [65]. Although 2R-HG appears to accumulate in cancer cells, which helps drive their proliferation, there has been a report that background physiological levels of 2R-HG can facilitate proliferation of primary fibroblasts [66]. The question has been posed, is IDH a tumor suppressor or an oncogene?…”

Section: (2r)-hydroxyglutaratementioning

confidence: 99%

Metabolic Rewiring and the Characterization of Oncometabolites

Beyoğlu

Idle

2021

Cancers

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The study of low-molecular-weight metabolites that exist in cells and organisms is known as metabolomics and is often conducted using mass spectrometry laboratory platforms. Definition of oncometabolites in the context of the metabolic phenotype of cancer cells has been accomplished through metabolomics. Oncometabolites result from mutations in cancer cell genes or from hypoxia-driven enzyme promiscuity. As a result, normal metabolites accumulate in cancer cells to unusually high concentrations or, alternatively, unusual metabolites are produced. The typical oncometabolites fumarate, succinate, (2R)-hydroxyglutarate and (2S)-hydroxyglutarate inhibit 2-oxoglutarate-dependent dioxygenases, such as histone demethylases and HIF prolyl-4-hydroxylases, together with DNA cytosine demethylases. As a result of the cancer cell acquiring this new metabolic phenotype, major changes in gene transcription occur and the modification of the epigenetic landscape of the cell promotes proliferation and progression of cancers. Stabilization of HIF1α through inhibition of HIF prolyl-4-hydroxylases by oncometabolites such as fumarate and succinate leads to a pseudohypoxic state that promotes inflammation, angiogenesis and metastasis. Metabolomics has additionally been employed to define the metabolic phenotype of cancer cells and patient biofluids in the search for cancer biomarkers. These efforts have led to the uncovering of the putative oncometabolites sarcosine, glycine, lactate, kynurenine, methylglyoxal, hypotaurine and (2R,3S)-dihydroxybutanoate, for which further research is required.

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“…As a result, such a microenvironment is permissible for tumor progression. For example, r -2HG via the stimulation of NF-κB elevates proliferation in a stromal niche for AML cells ( 26 ) and at relatively small concentrations promotes fibroblast proliferation ( 43 ).…”

Section: Hg As An Oncometabolitementioning

confidence: 99%

2-Hydroxyglutarate in Cancer Cells

Ježek

2020

Antioxidants & Redox Signaling

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Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1) R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2) R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to ''intermediate'' 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8 M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics. Antioxid. Redox Signal. 00, 000-000.

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Background Levels of Neomorphic 2-hydroxyglutarate Facilitate Proliferation of Primary Fibroblasts

Cited by 12 publications

References 45 publications

The Effects of Bilirubin and Lumirubin on Metabolic and Oxidative Stress Markers

The Effects of Bilirubin and Lumirubin on Metabolic and Oxidative Stress Markers

Metabolic Rewiring and the Characterization of Oncometabolites

2-Hydroxyglutarate in Cancer Cells

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