Supplementary Tables 1 - 4 from IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism

Grassian, Alexandra R.; Parker, Seth J.; Davidson, Shawn M.; Divakaruni, Ajit S.; Green, Courtney R.; Zhang, Xiamei; Slocum, Kelly L.; Pu, Minying; Lin, Fallon; Vickers, Chad; Joud-Caldwell, Carol; Chung, Franklin; Yin, Hong; Handly, Erika D.; Straub, Christopher; Growney, Joseph D.; Vander Heiden, Matthew G.; Murphy, Anne N.; Pagliarini, Raymond; Metallo, Christian M.

doi:10.1158/0008-5472.22404438.v1

00085472can140772t-sup-tabs1-4.pdf (92.17 kB)

Supplementary Tables 1 - 4 from IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism

journal contribution

posted on 2023-03-30, 22:52 authored by Alexandra R. Grassian, Seth J. Parker, Shawn M. Davidson, Ajit S. Divakaruni, Courtney R. Green, Xiamei Zhang, Kelly L. Slocum, Minying Pu, Fallon Lin, Chad Vickers, Carol Joud-Caldwell, Franklin Chung, Hong Yin, Erika D. Handly, Christopher Straub, Joseph D. Growney, Matthew G. Vander Heiden, Anne N. Murphy, Raymond Pagliarini, Christian M. Metallo

PDF file - 93KB, Estimates Fluxes for HCT116 Parental and IDH1 R132H/+ 2H1 cells under Normoxia and Hypoxia (2 percent Oxygen).

History

ARTICLE ABSTRACT

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. Cancer Res; 74(12); 3317–31. ©2014 AACR.