Cystathionine-γ-lyase drives antioxidant defense in cysteine-restricted IDH1-mutant astrocytomas

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Abstract
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzyme activity is crucial for the generation of reducing potential in normal cells, yet the impact of the mutation on the cellular antioxidant system in glioma is not understood. The aim of this study was to determine how glutathione (GSH), the main antioxidant in the brain, is maintained in IDH1-mutant gliomas, despite an altered NADPH/NADP balance.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Proteomics, metabolomics, metabolic tracer studies, genetic silencing, and drug targeting approaches in vitro and in vivo were applied. Analyses were done in clinical specimen of different glioma subtypes, in glioma patient-derived cell lines carrying the endogenous IDH1 mutation and corresponding orthotopic xenografts in mice.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We find that cystathionine-γ-lyase (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis, is specifically upregulated in IDH1-mutant astrocytomas. CSE inhibition sensitized these cells to cysteine depletion, an effect not observed in IDH1 wild-type gliomas. This correlated with an increase in reactive oxygen species and reduced GSH synthesis. Propargylglycine (PAG), a brain-penetrant drug specifically targeting CSE, led to delayed tumor growth in mice.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>We show that IDH1-mutant astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis via CSE to maintain the antioxidant defense, which highlights a novel metabolic vulnerability that may be therapeutically exploited.</jats:p> </jats:sec>
Autoren
  • Andrés Cano-Galiano
  • Anais Oudin
  • Fred Fack
  • Maria-Francesca Allega
  • David Sumpton
  • Elena Martinez-Garcia
  • Gunnar Dittmar
  • Ann-Christin Hau
  • Alfonso De Falco
  • Christel Herold-Mende
  • Rolf Bjerkvig
  • Johannes Meiser
  • Saverio Tardito
  • Simone P Niclou
DOI
10.1093/noajnl/vdab057
eISSN
2632-2498
Ausgabe der Veröffentlichung
1
Zeitschrift
Neuro-Oncology Advances
Sprache
en
Online publication date
2021
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Oxford University Press (OUP)
Herausgeber URL
http://dx.doi.org/10.1093/noajnl/vdab057
Datum der Datenerfassung
2021
Titel
Cystathionine-γ-lyase drives antioxidant defense in cysteine-restricted IDH1-mutant astrocytomas
Ausgabe der Zeitschrift
3

Datenquelle: Crossref

Andere Metadatenquellen:
Abstract
<h4>Background</h4>Mutations in isocitrate dehydrogenase 1 or 2 (<i>IDH1/2</i>) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzyme activity is crucial for the generation of reducing potential in normal cells, yet the impact of the mutation on the cellular antioxidant system in glioma is not understood. The aim of this study was to determine how glutathione (GSH), the main antioxidant in the brain, is maintained in IDH1-mutant gliomas, despite an altered NADPH/NADP balance.<h4>Methods</h4>Proteomics, metabolomics, metabolic tracer studies, genetic silencing, and drug targeting approaches in vitro and in vivo were applied. Analyses were done in clinical specimen of different glioma subtypes, in glioma patient-derived cell lines carrying the endogenous IDH1 mutation and corresponding orthotopic xenografts in mice.<h4>Results</h4>We find that cystathionine-γ-lyase (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis, is specifically upregulated in IDH1-mutant astrocytomas. CSE inhibition sensitized these cells to cysteine depletion, an effect not observed in IDH1 wild-type gliomas. This correlated with an increase in reactive oxygen species and reduced GSH synthesis. Propargylglycine (PAG), a brain-penetrant drug specifically targeting CSE, led to delayed tumor growth in mice.<h4>Conclusions</h4><i>W</i>e show that IDH1-mutant astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis via CSE to maintain the antioxidant defense, which highlights a novel metabolic vulnerability that may be therapeutically exploited.
Addresses
  • NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Autoren
  • Andrés Cano-Galiano
  • Anais Oudin
  • Fred Fack
  • Maria-Francesca Allega
  • David Sumpton
  • Elena Martinez-Garcia
  • Gunnar Dittmar
  • Ann-Christin Hau
  • Alfonso De Falco
  • Christel Herold-Mende
  • Rolf Bjerkvig
  • Johannes Meiser
  • Saverio Tardito
  • Simone P Niclou
DOI
10.1093/noajnl/vdab057
eISSN
2632-2498
Externe Identifier
  • PubMed Identifier: 34250481
  • PubMed Central ID: PMC8262642
Funding acknowledgements
  • CRUK Beatson Institute: A17196
  • Cancer Research UK: 23982
  • CANBIO DTU: PRIDE15/10675146
  • CRUK Core Funding: 23982
  • ATTRACT: A18/BM/11809970
  • National Research Fund: PRIDE15/10675146
Open access
true
ISSN
2632-2498
Ausgabe der Veröffentlichung
1
Zeitschrift
Neuro-oncology advances
Sprache
eng
Medium
Electronic-eCollection
Online publication date
2021
Open access status
Open Access
Paginierung
vdab057
Datum der Veröffentlichung
2021
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2021
Titel
Cystathionine-γ-lyase drives antioxidant defense in cysteine-restricted IDH1-mutant astrocytomas.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
3

Files

https://europepmc.org/articles/PMC8262642?pdf=render

Datenquelle: Europe PubMed Central

Abstract
BACKGROUND: Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzyme activity is crucial for the generation of reducing potential in normal cells, yet the impact of the mutation on the cellular antioxidant system in glioma is not understood. The aim of this study was to determine how glutathione (GSH), the main antioxidant in the brain, is maintained in IDH1-mutant gliomas, despite an altered NADPH/NADP balance. METHODS: Proteomics, metabolomics, metabolic tracer studies, genetic silencing, and drug targeting approaches in vitro and in vivo were applied. Analyses were done in clinical specimen of different glioma subtypes, in glioma patient-derived cell lines carrying the endogenous IDH1 mutation and corresponding orthotopic xenografts in mice. RESULTS: We find that cystathionine-γ-lyase (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis, is specifically upregulated in IDH1-mutant astrocytomas. CSE inhibition sensitized these cells to cysteine depletion, an effect not observed in IDH1 wild-type gliomas. This correlated with an increase in reactive oxygen species and reduced GSH synthesis. Propargylglycine (PAG), a brain-penetrant drug specifically targeting CSE, led to delayed tumor growth in mice. CONCLUSIONS: We show that IDH1-mutant astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis via CSE to maintain the antioxidant defense, which highlights a novel metabolic vulnerability that may be therapeutically exploited.
Autoren
  • Andrés Cano-Galiano
  • Anais Oudin
  • Fred Fack
  • Maria-Francesca Allega
  • David Sumpton
  • Elena Martinez-Garcia
  • Gunnar Dittmar
  • Ann-Christin Hau
  • Alfonso De Falco
  • Christel Herold-Mende
  • Rolf Bjerkvig
  • Johannes Meiser
  • Saverio Tardito
  • Simone P Niclou
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/34250481
DOI
10.1093/noajnl/vdab057
eISSN
2632-2498
Externe Identifier
  • PubMed Central ID: PMC8262642
Funding acknowledgements
  • Cancer Research UK: 23982
Ausgabe der Veröffentlichung
1
Zeitschrift
Neurooncol Adv
Schlüsselwörter
  • IDH mutation
  • antioxidant defense
  • cysteine
  • glioma
  • glutathione
  • transsulfuration pathway
Sprache
eng
Country
England
Paginierung
vdab057
PII
vdab057
Datum der Veröffentlichung
2021
Status
Published online
Titel
Cystathionine-γ-lyase drives antioxidant defense in cysteine-restricted IDH1-mutant astrocytomas.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
3

Datenquelle: PubMed

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