Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer

Abstract

NRF2 is emerging as a major regulator of cellular metabolism. However, most studies have been performed in cancer cells, where co-occurring mutations and tumor selective pressures complicate the influence of NRF2 on metabolism. Here we use genetically engineered, non-transformed primary murine cells to isolate the most immediate effects of NRF2 on cellular metabolism. We find that NRF2 promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1 (CDO1), which catalyzes the irreversible metabolism of cysteine to cysteine sulfinic acid (CSA). Notably, CDO1 is preferentially silenced by promoter methylation in human non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2. CDO1 silencing promotes proliferation of NSCLC by limiting the futile metabolism of cysteine to the wasteful and toxic byproducts CSA and sulfite (SO32-), and depletion of cellular NADPH. Thus, CDO1 is a metabolic liability for NSCLC cells with high intracellular cysteine, particularly NRF2/KEAP1 mutant cells.

Metabolic features of cancer cells in NRF2 addiction status

“…While the cysteine decomposition is coupled with mitochondrial bioenergetics in the cells with intact KEAP1-NRF2 system, in NRF2-addicted cancer cells, most of the available cysteine appears to flow into the anabolic pathway, namely, glutathione synthesis and leaves the catabolic pathway in mitochondria, which is consistent with the observation that mitochondrial respiration is limited in NRF2addicted cancer cells (Sayin et al 2017). Moreover, an alternative pathway of cysteine catabolism, which is mediated by CDO1, has been shown to be inactive in NRF2-addicted cancer cells due to DNA methylation at the CDO1 locus (Kang et al 2019). CDO1 converts cysteine to cysteine sulfinic acid, resulting in the limited availability of cysteine for the anabolic pathway.…”

Comprehensive Review of Methodology to Detect Reactive Oxygen Species (ROS) in Mammalian Species and Establish Its Relationship with Antioxidants and Cancer

“…In one of the models, elimination of KEAP1 was not chosen for Kras G12D or p53 flox/flox ; in fact the LKB1 flox/flox model was contrasted with other tumor suppressors [ 186 ]. While heterozygous KEAP1 R554Q loss-of-function mutant expression enhanced the size of tumor similar to the deletion study of Kras G12D ; the p53 flox/flox model homozygous KEAP1 R554Q expression antagonized the formation of the tumor [ 187 ]. For an in-depth insight into whether KEAP1 mutation or level of NRF2 activation have a distinct effect on the growth and progression of tumor, however, additional studies are needed for further understanding.…”

Amino acids in cancer

“…Cancer cells reprogram metabolism in ways that can meet their increased demand for amino acids 37,[111][112][113] . Amino acids can be taken up from the extracellular environment or, in the case of NEAAs, be synthesized by various reactions, including transaminase reactions.…”