Metabolism: Reprogramming metabolic flux in glioma
1
A new study has shown that growth of gliomas with isocitrate dehydro- genase 1 (IDH1) mutations is promoted by expression of glutamate dehydrogenase 2 (GLUD2) protein. IDH1 mutations are frequent in secondary glioblastomas but their functional significance has been unclear. IDH1 normally catalyses the conversion of isocitrate to α-ketoglutarate (αKG) but cancer- associated IDH1 mutations produce an alternative enzyme that converts αKG to 2-hydroxyglutarate (2HG). Previous studies have revealed that 2HG accumulation can exert oncogenic effects, but, paradoxi- cally, have demonstrated that IDH1 mutations can also exert growth-inhibitory effects. In order to determine promoters of growth in IDH1-mutated gliomas, Chen et al. established a glioma pro- genitor cell culture line using murine nestin-positive, Tp53-negative neural stem cells. IDH1 mutations in human gliomas co-segregate with p53 muta- tions, thus these glioma progenitor cells are relevant to human tumours. The authors examined the growth of glioma progenitor cells that also had either wild-type IDH1, shRNA- mediated knockdown of IDH1, or expression of the most common IDH1 mutant, IDH1-R132H. Interestingly, cells lacking IDH1 or with IDH1-R132H grew more slowly, and, as expected, mutant IDH1 cells had elevated levels of 2HG. However, growth defects in IDH1-mutant cells could be rescued with transfection of wild-type IDH1 in spite of enhanced accumulation of 2HG, suggesting that lack of αKG rather than the effects of 2HG is behind the growth defects in these cells. Consistent with previous studies, IDH1-mutant tumours continued to express normal levels of αKG. To determine whether other wild-type IDH proteins were upregulated to compensate for the lack of wild- type IDH1 in human tumours, the authors looked at expression profiling data from IDH1-mutant and IDH1 wild-type human gliomas. Although they did not observe an increase in expression in any of the IDH proteins, they did find increased expression of the GLUD1 and GLUD2 proteins. Knockdown of these proteins with shRNAs in xenograft tumours generated from a human IDH1-mutant glioma cell line resulted in decreased tumour volume as well as decreased tumour cell density. As the GLUD proteins catalyse the conversion of glutamate to αKG, the authors investigated whether ectopic expression of either GLUD1 or GLUD2 could rescue the growth inhibition caused by IDH1 mutation. GLUD2, but not GLUD1, rescued growth of IDH1-mutant cells and xenograft tumours, indicating that GLUD protein functions are not redundant. In addition, GLUD2 over- expression in IDH1 wild-type glioma cells had no effect, showing that the effects of GLUD2 are specific to IDH1-mutated cells. Thus, the pres- ence of GLUD2 in human brain may underlie vulnerability of this organ to IDH1-mutant driven oncogenesis. Glutamate is abundant in the brain, and the authors showed that extracellular glutamate enhanced growth of glioma progenitor cells, regardless of their IDH1 mutation status or whether GLUD1 or GLUD2 were overexpressed. Furthermore, using radiolabeled tracers, the authors showed that GLUD2 over- expression rescues metabolic flux (the incorporation of metabolites such as glucose and glutamine into lipids) in IDH1-mutant cells. This study provides further insight into the complexity of the metabolism of IDH1-mutant gliomas and identifies glutamate metabolism as a potential therapeutic target in these tumours. Isabel Lokody METABOLISM Reprogramming metabolic flux in glioma ORIGINAL RESEARCH PAPER Chen, R. et al. Hominoid-specific enzyme GLUD2 promotes growth of IDH1 R132H glioma. Proc. Natl Acad. Sci. USA http://dx.doi.org/10.1073/pnas.1409653111 (2014) the presence of GLUD2 in human brain may underlie vulnerability of this organ to IDH1- mutant driven oncogenesis Simon Bradbrook/NPG RESEARCH HIGHLIGHTS NATURE REVIEWS | CANCER VOLUME 14 | NOVEMBER 2014 Nature Reviews Cancer | AOP, published online 6 October 2014; doi:10.1038/nrc3840 © 2014 Macmillan Publishers Limited. All rights reserved
Transcript of Metabolism: Reprogramming metabolic flux in glioma
Nature Reviews | Cancer
A new study has shown that growth of gliomas with isocitrate dehydrogenase 1 (IDH1) mutations is promoted by expression of glutamate dehydrogenase 2 (GLUD2) protein.
IDH1 mutations are frequent in secondary glioblastomas but their functional significance has been unclear. IDH1 normally catalyses the conversion of isocitrate to αketoglutarate (αKG) but cancerassociated IDH1 mutations produce an alternative enzyme that converts αKG to 2hydroxyglutarate (2HG). Previous studies have revealed that 2HG accumulation can exert
oncogenic effects, but, paradoxically, have demonstrated that IDH1 mutations can also exert growthinhibitory effects.
In order to determine promoters of growth in IDH1mutated gliomas, Chen et al. established a glioma progenitor cell culture line using murine nestinpositive, Tp53negative neural stem cells. IDH1 mutations in human gliomas cosegregate with p53 mutations, thus these glioma progenitor cells are relevant to human tumours. The authors examined the growth of glioma progenitor cells that also had either wildtype IDH1, shRNAmediated knockdown of IDH1, or expression of the most common IDH1 mutant, IDH1R132H. Interestingly, cells lacking IDH1 or with IDH1R132H grew more slowly, and, as expected, mutant IDH1 cells had elevated levels of 2HG. However, growth defects in IDH1mutant cells could be rescued with transfection of wildtype IDH1 in spite of enhanced accumulation of 2HG, suggesting that lack of αKG rather than the effects of 2HG is behind the growth defects in these cells.
Consistent with previous studies, IDH1mutant tumours continued to express normal levels of αKG. To determine whether other wildtype IDH proteins were upregulated to compensate for the lack of wildtype IDH1 in human tumours, the authors looked at expression profiling data from IDH1mutant and IDH1 wildtype human gliomas. Although they did not observe an increase in expression in any of the IDH proteins, they did find increased expression of the GLUD1 and GLUD2 proteins. Knockdown of these proteins with shRNAs in xenograft tumours generated from
a human IDH1mutant glioma cell line resulted in decreased tumour volume as well as decreased tumour cell density.
As the GLUD proteins catalyse the conversion of glutamate to αKG, the authors investigated whether ectopic expression of either GLUD1 or GLUD2 could rescue the growth inhibition caused by IDH1 mutation. GLUD2, but not GLUD1, rescued growth of IDH1mutant cells and xenograft tumours, indicating that GLUD protein functions are not redundant. In addition, GLUD2 overexpression in IDH1 wildtype glioma cells had no effect, showing that the effects of GLUD2 are specific to IDH1mutated cells. Thus, the presence of GLUD2 in human brain may underlie vulnerability of this organ to IDH1mutant driven oncogenesis.
Glutamate is abundant in the brain, and the authors showed that extracellular glutamate enhanced growth of glioma progenitor cells, regardless of their IDH1 mutation status or whether GLUD1 or GLUD2 were overexpressed. Furthermore, using radiolabeled tracers, the authors showed that GLUD2 overexpression rescues metabolic flux (the incorporation of metabolites such as glucose and glutamine into lipids) in IDH1mutant cells.
This study provides further insight into the complexity of the metabolism of IDH1mutant gliomas and identifies glutamate metabolism as a potential therapeutic target in these tumours.
Isabel Lokody
M E TA B O L I S M
Reprogramming metabolic flux in glioma
ORIGINAL RESEARCH PAPER Chen, R. et al. Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma. Proc. Natl Acad. Sci. USA http://dx.doi.org/10.1073/pnas.1409653111 (2014)
the presence of GLUD2 in human brain may underlie vulnerability of this organ to IDH1-mutant driven oncogenesis
Sim
on B
radb
rook
/NPG
R E S E A R C H H I G H L I G H T S
NATURE REVIEWS | CANCER VOLUME 14 | NOVEMBER 2014
Nature Reviews Cancer | AOP, published online 6 October 2014; doi:10.1038/nrc3840
© 2014 Macmillan Publishers Limited. All rights reserved
