1. Biochemistry and Chemical Biology
  2. Cancer Biology
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Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer

  1. Yun Pyo Kang
  2. Laura Torrente
  3. Aimee Falzone
  4. Cody M Elkins
  5. Min Liu
  6. John M Asara
  7. Christian C Dibble
  8. Gina DeNicola  Is a corresponding author
  1. H Lee Moffitt Cancer Center and Research Institute, United States
  2. Beth Israel Deaconess Medical Center, United States
Research Article
  • Cited 24
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Cite this article as: eLife 2019;8:e45572 doi: 10.7554/eLife.45572

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.

Article and author information

Author details

  1. Yun Pyo Kang

    Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Laura Torrente

    Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Aimee Falzone

    Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Cody M Elkins

    Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Min Liu

    Proteomics and Metabolomics Core Facility, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. John M Asara

    Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Christian C Dibble

    Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Gina DeNicola

    Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
    For correspondence
    gina.denicola@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6611-6696

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.

Reviewing Editor

  1. Matthew G Vander Heiden, Massachusetts Institute of Technology, United States

Publication history

  1. Received: January 28, 2019
  2. Accepted: May 17, 2019
  3. Accepted Manuscript published: May 20, 2019 (version 1)
  4. Version of Record published: June 19, 2019 (version 2)
  5. Version of Record updated: October 18, 2019 (version 3)

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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