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
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.
- Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al.: An integrated genomic analysis of human glioblastoma multiforme. Science 2008, 321: 1807–1812. 10.1126/science.1164382View ArticlePubMedPubMed CentralGoogle Scholar
- Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al.: IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009, 360: 765–773. 10.1056/NEJMoa0808710View ArticlePubMedPubMed CentralGoogle Scholar
- Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al.: Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009, 462: 739–744. 10.1038/nature08617View ArticlePubMedPubMed CentralGoogle Scholar
- Borodovsky A, Seltzer MJ, Riggins GJ: Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2. Curr Opin Oncol 2012, 24: 83–89. 10.1097/CCO.0b013e32834d816aView ArticlePubMedPubMed CentralGoogle Scholar
- Venneti S, Thompson CB: Metabolic modulation of epigenetics in gliomas. Brain Pathol 2013, 23: 217–221. 10.1111/bpa.12022View ArticlePubMedPubMed CentralGoogle Scholar
- Reitman ZJ, Yan H: Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 2010, 102: 932–941. 10.1093/jnci/djq187View ArticlePubMedPubMed CentralGoogle Scholar
- Mirebeau-Prunier D, Le Pennec S, Jacques C, Fontaine JF, Gueguen N, Boutet-Bouzamondo N, et al.: Estrogen-related receptor alpha modulates lactate dehydrogenase activity in thyroid tumors. PLoS One 2013, 8: e58683. 10.1371/journal.pone.0058683View ArticlePubMedPubMed CentralGoogle Scholar
- Ho J, de Moura MB, Lin Y, Vincent G, Thorne S, Duncan LM, et al.: Importance of glycolysis and oxidative phosphorylation in advanced melanoma. Mol Cancer 2012, 11: 76. 10.1186/1476-4598-11-76View ArticlePubMedPubMed CentralGoogle Scholar
- McCleland ML, Adler AS, Deming L, Cosino E, Lee L, Blackwood EM, et al.: Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas. Clin Cancer Res 2013, 19: 773–784. 10.1158/1078-0432.CCR-12-2638View ArticlePubMedGoogle Scholar
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