TOF-SIMS analysis of an isocitrate dehydrogenase 1 mutation-associated oncometabolite in cancer cells

Jungdae Park, Hee Kyung Na, Hyun Kyong Shon, Hye Young Son, yongmin Huh, Sang Won Lee, Tae Geol Lee

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The development of analytical tools for accurate and sensitive detection of intracellular metabolites associated with mutated metabolic enzymes is important in cancer diagnosis and staging. The gene encoding the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is mutated in various cancers, and mutant IDH1 could represent a good biomarker and potent target for cancer therapy. Owing to a mutation in an important arginine residue in the catalytic pocket, mutant IDH1 catalyzes the production of 2-hydroxyglutarate (2-HG) instead of its wild type product α-ketoglutarate (α-KG), which is involved in multiple cellular pathways involving the hydroxylation of proteins, ribonucleic acid, and deoxyribose nucleic acid (DNA). Since 2-HG is an α-KG antagonist, inhibiting normal α-KG-dependent metabolism, high intracellular levels of 2-HG result in abnormal histone and DNA methylation. Therefore, accurate and sensitive analytical tools for the direct detection of 2-HG in cancer cells expressing mutant IDH1 would benefit this field, as it would minimize the need both for complicated experimental procedures and for large amounts of biological samples. Here, the authors describe a useful analytical method for the direct detection of 2-HG in lysates from a mutant IDH1-expressing cell line by time-of-flight secondary ion mass spectrometry (TOF-SIMS) analysis, a powerful surface analysis tool. In addition, the authors verified the efficacy of the specific mutant IDH1 inhibitor AGI-5198 by tracking the intracellular 2-HG concentration, which decreased in a dose-dependent manner. Our results demonstrate the large potential of TOF-SIMS as an analytical tool for the simple, direct detection of oncometabolites during cancer diagnosis, and for verifying the efficiency of the targeted cancer drugs.

Original languageEnglish
Article number03B404
JournalBiointerphases
Volume13
Issue number3
DOIs
Publication statusPublished - 2018 Jun 1

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Secondary Ion Mass Spectrometry
Isocitrate Dehydrogenase
dehydrogenases
mutations
Secondary ion mass spectrometry
secondary ion mass spectrometry
cancer
Cells
Mutation
Deoxyribose
Neoplasms
Nucleic acids
nucleic acids
Nucleic Acids
enzymes
Enzymes
ribonucleic acids
Hydroxylation
Arginine
Gene encoding

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biomaterials
  • Materials Science(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Park, Jungdae ; Na, Hee Kyung ; Shon, Hyun Kyong ; Son, Hye Young ; Huh, yongmin ; Lee, Sang Won ; Lee, Tae Geol. / TOF-SIMS analysis of an isocitrate dehydrogenase 1 mutation-associated oncometabolite in cancer cells. In: Biointerphases. 2018 ; Vol. 13, No. 3.
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TOF-SIMS analysis of an isocitrate dehydrogenase 1 mutation-associated oncometabolite in cancer cells. / Park, Jungdae; Na, Hee Kyung; Shon, Hyun Kyong; Son, Hye Young; Huh, yongmin; Lee, Sang Won; Lee, Tae Geol.

In: Biointerphases, Vol. 13, No. 3, 03B404, 01.06.2018.

Research output: Contribution to journalArticle

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AU - Park, Jungdae

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AU - Shon, Hyun Kyong

AU - Son, Hye Young

AU - Huh, yongmin

AU - Lee, Sang Won

AU - Lee, Tae Geol

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AB - The development of analytical tools for accurate and sensitive detection of intracellular metabolites associated with mutated metabolic enzymes is important in cancer diagnosis and staging. The gene encoding the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is mutated in various cancers, and mutant IDH1 could represent a good biomarker and potent target for cancer therapy. Owing to a mutation in an important arginine residue in the catalytic pocket, mutant IDH1 catalyzes the production of 2-hydroxyglutarate (2-HG) instead of its wild type product α-ketoglutarate (α-KG), which is involved in multiple cellular pathways involving the hydroxylation of proteins, ribonucleic acid, and deoxyribose nucleic acid (DNA). Since 2-HG is an α-KG antagonist, inhibiting normal α-KG-dependent metabolism, high intracellular levels of 2-HG result in abnormal histone and DNA methylation. Therefore, accurate and sensitive analytical tools for the direct detection of 2-HG in cancer cells expressing mutant IDH1 would benefit this field, as it would minimize the need both for complicated experimental procedures and for large amounts of biological samples. Here, the authors describe a useful analytical method for the direct detection of 2-HG in lysates from a mutant IDH1-expressing cell line by time-of-flight secondary ion mass spectrometry (TOF-SIMS) analysis, a powerful surface analysis tool. In addition, the authors verified the efficacy of the specific mutant IDH1 inhibitor AGI-5198 by tracking the intracellular 2-HG concentration, which decreased in a dose-dependent manner. Our results demonstrate the large potential of TOF-SIMS as an analytical tool for the simple, direct detection of oncometabolites during cancer diagnosis, and for verifying the efficiency of the targeted cancer drugs.

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