Journal Article

Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer

Wu, Warren L, Ubriaco, Julian, Sayin, Volkan I, Thomas, Craig J, Possemato, Richard, LeBoeuf, Sarah E, Vander Heiden, Matthew G, Singh, Simranjit X, Guzelhan, Betul S, Morris, Patrick J, Alvarez, Samantha W, Karagiannis, Dimitris, Muir, Alexander, Davidson, Shawn M, Biancur, Douglas, Papagiannakopoulos, Thales, Zavitsanou, Anastasia Maria, Karakousi, Triantafyllia R

2017

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Amino acids / Animals / Antioxidants / Antioxidants (Nutrients) / Antioxidants - metabolism / Biotechnology industries / Cancer / Cancer Biology / Cancer cells / Carbon - metabolism / Cell Line, Tumor / Cell Proliferation / Cell Survival / Characterization / Clinical trials / Enzymes / Gene expression / Genetic aspects / Glutamate / Glutamic Acid - metabolism / Glutamine / Glutathione / Glutathione - metabolism / Homeostasis / Humans / International economic relations / Legal liability / Medical research / Metabolism / Metabolites / Mice / Mutation / Neoplasms - pathology / NF-E2-Related Factor 2 - metabolism / Physiological aspects / Reactive oxygen species / Secretion / Tricarboxylic acid cycle / Tumor cells / Tumorigenesis / Tumors