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

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

来源：eLife, 2017, 6: e28083.

DOI：10.7554/eLife.28083

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 x(c)(-) 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.

• 出版日期2017-10-2