Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer
Name
elife-28083-v1.pdf
Size
928.61 KB
Format
Adobe PDF
Checksum (MD5)
1012cf18ff9612da3d426a1dc7115b16
Author(s)
Sayin, Volkan I
LeBoeuf, Sarah E
Singh, Simranjit X
Biancur, Douglas
Guzelhan, Betul S
Alvarez, Samantha W
Wu, Warren L
Karakousi, Triantafyllia R
Zavitsanou, Anastasia Maria
Ubriaco, Julian
Date Issued
October 2017
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Sayin, Volkan I, Sarah E LeBoeuf, Simranjit X Singh, Shawn M Davidson, Douglas Biancur, Betul S Guzelhan, Samantha W Alvarez, et al. “Activation of the NRF2 Antioxidant Program Generates an Imbalance in Central Carbon Metabolism in Cancer.” eLife 6 (October 2017): e28083
Version
Final published version
Abstract
During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by xc-antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
CC0 1.0 Universal (CC0 1.0)
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.7554/ELIFE.28083
