| Autor: |
Christian M. Metallo, Raymond Pagliarini, Anne N. Murphy, Matthew G. Vander Heiden, Joseph D. Growney, Christopher Straub, Erika D. Handly, Hong Yin, Franklin Chung, Carol Joud-Caldwell, Chad Vickers, Fallon Lin, Minying Pu, Kelly L. Slocum, Xiamei Zhang, Courtney R. Green, Ajit S. Divakaruni, Shawn M. Davidson, Seth J. Parker, Alexandra R. Grassian |
| Rok vydání: |
2023 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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