Journal
CELL REPORTS
Volume 19, Issue 9, Pages 1858-1873Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.05.014
Keywords
-
Categories
Funding
- Center for Cancer Nanotechnology Excellence (CCNE) initiative of the NIH [U54 CA199091]
- Alliance for Cancer Gene Therapy (ACGT)
- Dixon Translational Research Grants Initiative of the Northwestern Memorial Foundation
- Coffman Charitable Trust
- National Cancer Institute (NCI)/NIH training [T32CA09560]
- NCI [P30 CA060553]
- NIH Common Funds Project [U24 DK097153]
- U.S. Army Research Office
- U.S. Army Medical Research and Material Command
- Northwestern University
Ask authors/readers for more resources
Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBMs. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs the survival of animal subjects bearing patient-derived xenografts (PDXs). On a molecular level, diminished IDH1 activity results in reduced a-ketoglutarate (alpha KG) and NADPH production, paralleled by deficient carbon flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common metabolic adaptation by GBMs to support macromolecular synthesis, aggressive growth, and therapy resistance.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available