1. Biochemistry and Chemical Biology
  2. Cancer Biology

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
https://doi.org/10.7554/eLife.45572
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

Reviewing Editor

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

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.

Version 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

  • 6,084
    views
  • 880
    downloads
  • 74
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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

Share this article

https://doi.org/10.7554/eLife.45572

Categories and tags

Research organisms

Further reading

    1. Biochemistry and Chemical Biology
    2. Plant Biology

    Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling

    Henning Mühlenbeck, Yuko Tsutsui ... Cyril Zipfel
    Research Article

    Transmembrane signaling by plant receptor kinases (RKs) has long been thought to involve reciprocal trans-phosphorylation of their intracellular kinase domains. The fact that many of these are pseudokinase domains, however, suggests that additional mechanisms must govern RK signaling activation. Non-catalytic signaling mechanisms of protein kinase domains have been described in metazoans, but information is scarce for plants. Recently, a non-catalytic function was reported for the leucine-rich repeat (LRR)-RK subfamily XIIa member EFR (elongation factor Tu receptor) and phosphorylation-dependent conformational changes were proposed to regulate signaling of RKs with non-RD kinase domains. Here, using EFR as a model, we describe a non-catalytic activation mechanism for LRR-RKs with non-RD kinase domains. EFR is an active kinase, but a kinase-dead variant retains the ability to enhance catalytic activity of its co-receptor kinase BAK1/SERK3 (brassinosteroid insensitive 1-associated kinase 1/somatic embryogenesis receptor kinase 3). Applying hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis and designing homology-based intragenic suppressor mutations, we provide evidence that the EFR kinase domain must adopt its active conformation in order to activate BAK1 allosterically, likely by supporting αC-helix positioning in BAK1. Our results suggest a conformational toggle model for signaling, in which BAK1 first phosphorylates EFR in the activation loop to stabilize its active conformation, allowing EFR in turn to allosterically activate BAK1.

    1. Biochemistry and Chemical Biology
    2. Neuroscience

    Alzheimer’s disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling

    Katarzyna Marta Zoltowska, Utpal Das ... Lucía Chávez-Gutiérrez
    Research Article

    Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aβ, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aβ on γ-secretases. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17–42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.