Dataset Information

Comprehensive Metabolomic Analysis of IDH1^R132H Clinical Glioma Samples Reveals Suppression of ?-oxidation Due to Carnitine Deficiency.

ABSTRACT: Gliomas with Isocitrate dehydrogenase 1 (IDH1) mutation have alterations in several enzyme activities, resulting in various metabolic changes. The aim of this study was to determine a mechanism for the better prognosis of gliomas with IDH mutation by performing metabolomic analysis. To understand the metabolic state of human gliomas, we analyzed clinical samples obtained from surgical resection of glioma patients (grades II-IV) with or without the IDH1 mutation, and compared the results with U87 glioblastoma cells overexpressing IDH1 or IDH1^R132H. In clinical samples of gliomas with IDH1 mutation, levels of D-2-hydroxyglutarate (D-2HG) were increased significantly compared with gliomas without IDH mutation. Gliomas with IDH mutation also showed decreased intermediates in the tricarboxylic acid cycle and pathways involved in the production of energy, amino acids, and nucleic acids. The marked difference in the metabolic profile in IDH mutant clinical glioma samples compared with that of mutant IDH expressing cells includes a decrease in ?-oxidation due to acyl-carnitine and carnitine deficiencies. These metabolic changes may explain the lower cell division rate observed in IDH mutant gliomas and may provide a better prognosis in IDH mutant gliomas.

SUBMITTER: Miyata S

PROVIDER: S-EPMC6611790 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Comprehensive Metabolomic Analysis of IDH1<sup>R132H</sup> Clinical Glioma Samples Reveals Suppression of β-oxidation Due to Carnitine Deficiency.

Miyata Satsuki S Tominaga Kaoru K Sakashita Eiji E Urabe Masashi M Onuki Yoshiyuki Y Gomi Akira A Yamaguchi Takashi T Mieno Makiko M Mizukami Hiroaki H Kume Akihiro A Ozawa Keiya K Watanabe Eiju E Kawai Kensuke K Endo Hitoshi H

Scientific reports 20190705 1

Gliomas with Isocitrate dehydrogenase 1 (IDH1) mutation have alterations in several enzyme activities, resulting in various metabolic changes. The aim of this study was to determine a mechanism for the better prognosis of gliomas with IDH mutation by performing metabolomic analysis. To understand the metabolic state of human gliomas, we analyzed clinical samples obtained from surgical resection of glioma patients (grades II-IV) with or without the IDH1 mutation, and compared the results with U87 ...[more]

PMID: 31278288

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Project description:Heterozygous isocitrate dehydrogenase (IDH) R132H mutation (IDH1R132H/WT) is an early event during gliomagenesis. Clinically, patients with glioma carrying mutant IDH1 respond better to antitumor therapies. However, the mechanism by which IDH1 mutations contribute to gliomagenesis and therapeutic response remains elusive. Here we report that senescence is involved in the improved therapeutic responses of mutant IDH1 glioma cells. Knocking-in IDH1R132H/WT in glioma cells significantly enhanced gliomas cell senescence in response to temozolomide and radiation via a DNA-damage mediated mechanism. We further asked if senescence plays a role in IDH1R132H/WT-induced gliomagenesis. Together with ATRX knockout and p53/RB loss, IDH1R132H/WT transformed nonneoplastic human astroglial cells to form tumors in mouse brains. In-depth characterization revealed that a subset of these precancerous cells underwent senescence-like phenotypic changes, including flat and enlarged-cell morphology, increased senescence marker expression, decreased cell proliferation, and cell-cycle arrest at the G2-M phase. Mechanistic studies indicated that the combination of glioma driver genes (p53/RB/IDH1/ATRX) dramatically increased DNA damage and activated DNAdamage response (DDR) pathways ATR/ATR and Chk1/Chk2 in senescent cells. To determine how senescent cells drive tumor formation, we investigated non-cell-autonomous mechanisms such as senescence-associated secretory phenotype (SASP), a panel of proinflammatory and tissue-remodeling factors implicated in a tumor-permissive microenvironment. We found that astroglial cells carrying p53/RB/ATRX loss and IDH1R132H/WT upregulated key factors in SASP via an epigenetic-mediated mechanism. Our work suggests that drugs that specifically eliminate senescent cells could help kill precancerous cells and senescent tumor cells following antitumor therapies. IMPLICATIONS: The mechanisms by which IDH1 mutations contribute to gliomagenesis and therapeutic responses remain incompletely characterized; this work reveals senescence as a novel mechanism of IDH-mutant-mediated biological impact and describes new therapeutic opportunities concerning IDH1-mutant gliomas.

Dataset Information

Comprehensive Metabolomic Analysis of IDH1^R132H Clinical Glioma Samples Reveals Suppression of ?-oxidation Due to Carnitine Deficiency.

Publications

Comprehensive Metabolomic Analysis of IDH1<sup>R132H</sup> Clinical Glioma Samples Reveals Suppression of β-oxidation Due to Carnitine Deficiency.

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Dataset Information

Comprehensive Metabolomic Analysis of IDH1R132H Clinical Glioma Samples Reveals Suppression of ?-oxidation Due to Carnitine Deficiency.

Publications

Comprehensive Metabolomic Analysis of IDH1<sup>R132H</sup> Clinical Glioma Samples Reveals Suppression of β-oxidation Due to Carnitine Deficiency.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Comprehensive Metabolomic Analysis of IDH1^R132H Clinical Glioma Samples Reveals Suppression of ?-oxidation Due to Carnitine Deficiency.