- Letter to the Editor
- Open Access
Metabolic alterations due to IDH1 mutation in glioma: opening for therapeutic opportunities?
© Mustafa et al.; licensee BioMed Central Ltd. 2014
- Received: 25 November 2013
- Accepted: 2 January 2014
- Published: 9 January 2014
- Pyruvate Kinase
- IDH1 Mutation
- Aerobic Glycolysis
Recently heterozygous mutations in the active site of the enzyme isocitrate dehydrogenase 1 (IDH1) were discovered in glioblastomas . In cohorts of glioma patients the IDH1 mutation appeared to be a strong predictor of clinical outcome, overruling histological malignancy grade . IDH1 is an enzyme of the tricarboxylic acid (TCA) cycle and is located in the cytosol, where it produces NADPH by transforming isocitrate into α-ketoglutarate. Because the mutant enzyme displays neomorphic activity through NADPH-dependent transformation of α-ketoglutarate into 2-hydroxyglutarate (2HG), the tumorigenic role of the increased levels of 2HG has become a target of speculation . IDH1 mutation alters the cellular metabolism and epigenetic phenotype influencing cellular proliferation. IDH1 mutation infers increased levels of D2HGDH leading to the inhibition of DNA and histone demethylating enzymes, resulting in the glioma-CpG island phenotype . Altered concentrations of pyruvate kinase M2 play also a role in histone modifications which are associated with the transcription of the proliferation-related cyclin D1 and c-MYC . In addition, IDH1 mutant cells show alterations in glutamine, fatty acid and citrate synthesis pathways, which all may have their influence on cellular proliferation .
Percentages of glioma types and grades
IDH1 wild type
We conclude that gliomas with IDH1 mutation normalize their glucose metabolism, which appears to result in a slower tumor progression. Depending on the IDH1 status of the tumor, specific interference with the glucose metabolism and aerobic glycolysis should therefore be considered for future therapeutic strategies.
The authors thank Mr. M. van der Weiden for his technical assistance and Mr. F. van der Panne for assistance with the photography.
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