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

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.

SUBMITTER: Sayin VI

PROVIDER: S-EPMC5624783 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Sayin Volkan I VI LeBoeuf Sarah E SE Singh Simranjit X SX Davidson Shawn M SM Biancur Douglas D Guzelhan Betul S BS Alvarez Samantha W SW Wu Warren L WL Karakousi Triantafyllia R TR Zavitsanou Anastasia Maria AM Ubriaco Julian J Muir Alexander A Karagiannis Dimitris D Morris Patrick J PJ Thomas Craig J CJ Possemato Richard R Vander Heiden Matthew G MG Papagiannakopoulos Thales T

eLife 20171002

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 ...[more]

PMID: 28967864

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Project description:Viruses can manipulate the host metabolism to achieve optimal replication conditions, and central carbon metabolism (CCM) pathways are often crucial in determining viral infections. Feline calicivirus (FCV), a diminutive RNA viral agent, induces upper respiratory tract infections in feline hosts, with highly pathogenic strains capable of precipitating systemic infections and subsequent host cell necrosis, thereby presenting a formidable challenge to feline survival and protection. However, the relationship between FCV and host cell central carbon metabolism (CCM) remains unclear, and the precise pathogenic mechanisms of FCV are yet to be elucidated. Upon FCV infection of Crandell-Rees Feline Kidney (CRFK) cells, an enhanced cellular uptake of glucose and glutamine was observed. Metabolomics analyses disclosed pronounced alterations in the central carbon metabolism of the infected cells. FCV infection was found to augment glycolytic activity while sustaining the tricarboxylic acid (TCA) cycle flux, with cellular ATP levels remaining invariant. Concurrently, both glutamine metabolism and the flux of the pentose phosphate pathway (PPP) were noted to be intensified. The application of various inhibitory agents targeting glycolysis, glutamine metabolism, and the PPP resulted in a significant suppression of FCV proliferation. Experiments involving glucose and glutamine deprivation demonstrated that the absence of either nutrient markedly curtailed FCV replication. Collectively, these findings suggest a critical interplay between central carbon metabolism and FCV proliferation. FCV infection stimulates CRFK cells to augment glucose and glutamine uptake, thereby supplying the necessary metabolic substrates and energy for viral replication. During the infection, glutamine emerges as the primary energy substrate, ensuring ATP production and energy homeostasis, while glucose is predominantly channeled into the pentose phosphate pathway to facilitate nucleotide synthesis.

Dataset Information

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

Publications

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

Similar Datasets

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