Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1

Meghan J. Seltzer, Bryson D. Bennett, Avadhut D. Joshi, Ping Gao, Ajit G. Thomas, Dana V. Ferraris, Takashi Tsukamoto, Camilo Rojas, Barbara Slusher, Joshua D. Rabinowitz, Chi V. Dang, Gregory J Riggins

Research output: Contribution to journalArticle

Abstract

Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require α-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to α-KG. Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido- 1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous α-KG. BPTES inhibited glutaminase activity, lowered glutamate and α-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)8981-8987
Number of pages7
JournalCancer Research
Volume70
Issue number22
DOIs
StatePublished - Nov 15 2010

Fingerprint

Glutaminase
Isocitrate Dehydrogenase
Glioma
Growth
Glutamine
Glutamic Acid
Mutation
Glioblastoma
Acute Myeloid Leukemia
Small Interfering RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Seltzer, M. J., Bennett, B. D., Joshi, A. D., Gao, P., Thomas, A. G., Ferraris, D. V., ... Riggins, G. J. (2010). Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Research, 70(22), 8981-8987. https://doi.org/10.1158/0008-5472.CAN-10-1666

Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. / Seltzer, Meghan J.; Bennett, Bryson D.; Joshi, Avadhut D.; Gao, Ping; Thomas, Ajit G.; Ferraris, Dana V.; Tsukamoto, Takashi; Rojas, Camilo; Slusher, Barbara; Rabinowitz, Joshua D.; Dang, Chi V.; Riggins, Gregory J.

In: Cancer Research, Vol. 70, No. 22, 15.11.2010, p. 8981-8987.

Research output: Contribution to journalArticle

Seltzer, MJ, Bennett, BD, Joshi, AD, Gao, P, Thomas, AG, Ferraris, DV, Tsukamoto, T, Rojas, C, Slusher, B, Rabinowitz, JD, Dang, CV & Riggins, GJ 2010, 'Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1', Cancer Research, vol. 70, no. 22, pp. 8981-8987. https://doi.org/10.1158/0008-5472.CAN-10-1666
Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Research. 2010 Nov 15;70(22):8981-8987. https://doi.org/10.1158/0008-5472.CAN-10-1666
Seltzer, Meghan J. ; Bennett, Bryson D. ; Joshi, Avadhut D. ; Gao, Ping ; Thomas, Ajit G. ; Ferraris, Dana V. ; Tsukamoto, Takashi ; Rojas, Camilo ; Slusher, Barbara ; Rabinowitz, Joshua D. ; Dang, Chi V. ; Riggins, Gregory J. / Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. In: Cancer Research. 2010 ; Vol. 70, No. 22. pp. 8981-8987.
@article{b12253acb9da4225a8608fdc185d5431,
title = "Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1",
abstract = "Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require α-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to α-KG. Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido- 1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous α-KG. BPTES inhibited glutaminase activity, lowered glutamate and α-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy.",
author = "Seltzer, {Meghan J.} and Bennett, {Bryson D.} and Joshi, {Avadhut D.} and Ping Gao and Thomas, {Ajit G.} and Ferraris, {Dana V.} and Takashi Tsukamoto and Camilo Rojas and Barbara Slusher and Rabinowitz, {Joshua D.} and Dang, {Chi V.} and Riggins, {Gregory J}",
year = "2010",
month = "11",
day = "15",
doi = "10.1158/0008-5472.CAN-10-1666",
language = "English (US)",
volume = "70",
pages = "8981--8987",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "22",

}

TY - JOUR

T1 - Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1

AU - Seltzer, Meghan J.

AU - Bennett, Bryson D.

AU - Joshi, Avadhut D.

AU - Gao, Ping

AU - Thomas, Ajit G.

AU - Ferraris, Dana V.

AU - Tsukamoto, Takashi

AU - Rojas, Camilo

AU - Slusher, Barbara

AU - Rabinowitz, Joshua D.

AU - Dang, Chi V.

AU - Riggins, Gregory J

PY - 2010/11/15

Y1 - 2010/11/15

N2 - Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require α-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to α-KG. Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido- 1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous α-KG. BPTES inhibited glutaminase activity, lowered glutamate and α-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy.

AB - Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require α-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to α-KG. Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido- 1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous α-KG. BPTES inhibited glutaminase activity, lowered glutamate and α-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy.

UR - http://www.scopus.com/inward/record.url?scp=78549283855&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78549283855&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-1666

DO - 10.1158/0008-5472.CAN-10-1666

M3 - Article

C2 - 21045145

AN - SCOPUS:78549283855

VL - 70

SP - 8981

EP - 8987

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 22

ER -