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

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

  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.

Metrics

  • 4,558
    Page views
  • 684
    Downloads
  • 40
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2019)
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

    1. Biochemistry and Chemical Biology
    Kanwal Kayastha et al.
    Research Article

    Lactate oxidation with NAD+ as electron acceptor is a highly endergonic reaction. Some anaerobic bacteria overcome the energetic hurdle by flavin-based electron bifurcation/confurcation (FBEB/FBEC) using a lactate dehydrogenase (Ldh) in concert with the electron-transferring proteins EtfA and EtfB. The electron cryo-microscopically characterized (Ldh-EtfAB)2 complex of Acetobacterium woodii at 2.43 Å resolution consists of a mobile EtfAB shuttle domain located between the rigid central Ldh and the peripheral EtfAB base units. The FADs of Ldh and the EtfAB shuttle domain contact each other thereby forming the D (dehydrogenation-connected) state. The intermediary Glu37 and Glu139 may harmonize the redox potentials between the FADs and the pyruvate/lactate pair crucial for FBEC. By integrating Alphafold2 calculations a plausible novel B (bifurcation-connected) state was obtained allowing electron transfer between the EtfAB base and shuttle FADs. Kinetic analysis of enzyme variants suggests a correlation between NAD+ binding site and D-to-B-state transition implicating a 75° rotation of the EtfAB shuttle domain. The FBEC inactivity when truncating the ferredoxin domain of EtfA substantiates its role as redox relay. Lactate oxidation in Ldh is assisted by the catalytic base His423 and a metal center. On this basis, a comprehensive catalytic mechanism of the FBEC process was proposed.