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.
