IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism
Author(s)Grassian, A. R.; Parker, S. J.; Divakaruni, A. S.; Green, C. R.; Zhang, X.; Slocum, K. L.; Pu, M.; Lin, F.; Vickers, C.; Joud-Caldwell, C.; Chung, F.; Yin, H.; Handly, E. D.; Straub, C.; Growney, J. D.; Murphy, A. N.; Pagliarini, R.; Metallo, C. M.; Davidson, Shawn M; Vander Heiden, Matthew G.; ... Show more Show less
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Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed 13C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology
American Association for Cancer Research
Grassian, A. R. et al. “IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism.” Cancer Research 74.12 (2014): 3317–3331.
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