Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation

Fumiharu Ohka, Maki Ito, Melissa Ranjit, Takeshi Senga, Ayako Motomura, Kazuya Motomura, Kaori Saito, Keiko Kato, Yukinari Kato, Toshihiko Wakabayashi, Tomoyoshi Soga, Atsushi Natsume

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Isocitrate dehydrogenase 1 (IDH1), which localizes to the cytosol and peroxisomes, catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and in parallel converts NADP+ to NADPH. IDH1 mutations are frequently detected in grades 2-4 gliomas and in acute myeloid leukemias (AML). Mutations of IDH1 have been identified at codon 132, with arginine being replaced with histidine in most cases. Mutant IDH1 gains novel enzyme activity converting α-KG to d-2-hydroxyglutarate (2-HG) which acts as a competitive inhibitor of α-KG. As a result, the activity of α-KG-dependent enzyme is reduced. Based on these findings, 2-HG has been proposed to be an oncometabolite. In this study, we established HEK293 and U87 cells that stably expressed IDH1-WT and IDH1-R132H and investigated the effect of glutaminase inhibition on cell proliferation with 6-diazo-5-oxo-l-norleucine (DON). We found that cell proliferation was suppressed in IDH1-R132H cells. The addition of α-KG restored cell proliferation. The metabolic features of 33 gliomas with wild type IDH1 (IDH1-WT) and with IDH1-R132H mutation were examined by global metabolome analysis using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). We showed that the 2-HG levels were highly elevated in gliomas with IDH1-R132H mutation. Intriguingly, in gliomas with IDH1-R132H, glutamine and glutamate levels were significantly reduced which implies replenishment of α-KG by glutaminolysis. Based on these results, we concluded that glutaminolysis is activated in gliomas with IDH1-R132H mutation and that development of novel therapeutic approaches targeting activated glutaminolysis is warranted.

Original languageEnglish
Pages (from-to)5911-5920
Number of pages10
JournalTumor Biology
Volume35
Issue number6
DOIs
Publication statusPublished - 2014

Fingerprint

Activation Analysis
Isocitrate Dehydrogenase
Metabolome
Glioma
Mutation
Cell Proliferation
NADP
Diazooxonorleucine
Glutaminase
Decarboxylation
Peroxisomes
HEK293 Cells
Capillary Electrophoresis
Enzymes
Glutamine
Histidine
Acute Myeloid Leukemia
Codon
Cytosol
Arginine

Keywords

  • Glioma
  • Glutaminolysis
  • IDH1 mutation
  • Metabolome

ASJC Scopus subject areas

  • Cancer Research

Cite this

Ohka, F., Ito, M., Ranjit, M., Senga, T., Motomura, A., Motomura, K., ... Natsume, A. (2014). Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. Tumor Biology, 35(6), 5911-5920. https://doi.org/10.1007/s13277-014-1784-5

Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. / Ohka, Fumiharu; Ito, Maki; Ranjit, Melissa; Senga, Takeshi; Motomura, Ayako; Motomura, Kazuya; Saito, Kaori; Kato, Keiko; Kato, Yukinari; Wakabayashi, Toshihiko; Soga, Tomoyoshi; Natsume, Atsushi.

In: Tumor Biology, Vol. 35, No. 6, 2014, p. 5911-5920.

Research output: Contribution to journalArticle

Ohka, F, Ito, M, Ranjit, M, Senga, T, Motomura, A, Motomura, K, Saito, K, Kato, K, Kato, Y, Wakabayashi, T, Soga, T & Natsume, A 2014, 'Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation', Tumor Biology, vol. 35, no. 6, pp. 5911-5920. https://doi.org/10.1007/s13277-014-1784-5
Ohka, Fumiharu ; Ito, Maki ; Ranjit, Melissa ; Senga, Takeshi ; Motomura, Ayako ; Motomura, Kazuya ; Saito, Kaori ; Kato, Keiko ; Kato, Yukinari ; Wakabayashi, Toshihiko ; Soga, Tomoyoshi ; Natsume, Atsushi. / Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. In: Tumor Biology. 2014 ; Vol. 35, No. 6. pp. 5911-5920.
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