Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer
- H Lee Moffitt Cancer Center and Research Institute, United States
- Beth Israel Deaconess Medical Center, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1c and Supplemental Figure 1a.
Article and author information
Author details
Funding
National Cancer Institute (R37-CA230042)
- Gina DeNicola
American Lung Association (LCDA-498544)
- Gina DeNicola
Moffitt Cancer Center (Milestone Award)
- Gina DeNicola
American Cancer Society (Institutional Research Grant)
- Gina DeNicola
National Cancer Institute (R00-CA194314)
- Christian C Dibble
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were housed and bred in accordance with the ethical regulations and approval of the IACUC (protocol # R IS00003893). Lung tumor formation was induced by intranasal installation of 2.5 x 107 PFU adenoviral-Cre (University of Iowa) as described previously (Jackson et al., 2001). Viral infections were performed under isofluorane anesthesia, and every effort was made to minimize suffering.
Copyright
© 2019, Kang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer
eLife 8:e45572.
https://doi.org/10.7554/eLife.45572
Further reading
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- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
Teichoic acids (TA) are linear phospho-saccharidic polymers and important constituents of the cell envelope of Gram-positive bacteria, either bound to the peptidoglycan as wall teichoic acids (WTA) or to the membrane as lipoteichoic acids (LTA). The composition of TA varies greatly but the presence of both WTA and LTA is highly conserved, hinting at an underlying fundamental function that is distinct from their specific roles in diverse organisms. We report the observation of a periplasmic space in Streptococcus pneumoniae by cryo-electron microscopy of vitreous sections. The thickness and appearance of this region change upon deletion of genes involved in the attachment of TA, supporting their role in the maintenance of a periplasmic space in Gram-positive bacteria as a possible universal function. Consequences of these mutations were further examined by super-resolved microscopy, following metabolic labeling and fluorophore coupling by click chemistry. This novel labeling method also enabled in-gel analysis of cell fractions. With this approach, we were able to titrate the actual amount of TA per cell and to determine the ratio of WTA to LTA. In addition, we followed the change of TA length during growth phases, and discovered that a mutant devoid of LTA accumulates the membrane-bound polymerized TA precursor.
