1. Cancer Biology
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Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition

  1. Alexander Muir
  2. Laura V Danai
  3. Dan Y Gui
  4. Chiara Y Waingarten
  5. Caroline A Lewis
  6. Matthew G Vander Heiden  Is a corresponding author
  1. Massachusetts Institute of Technology, United States
Research Article
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Cite this article as: eLife 2017;6:e27713 doi: 10.7554/eLife.27713

Abstract

Many mammalian cancer cell lines depend on glutamine as a major tri-carboxylic acid (TCA) cycle anaplerotic substrate to support proliferation. However, some cell lines that depend on glutamine anaplerosis in culture rely less on glutamine catabolism to proliferate in vivo. We sought to understand the environmental differences that cause differential dependence on glutamine for anaplerosis. We find that cells cultured in adult bovine serum, which better reflects nutrients available to cells in vivo, exhibit decreased glutamine catabolism and reduced reliance on glutamine anaplerosis compared to cells cultured in standard tissue culture conditions. We find that levels of a single nutrient, cystine, accounts for the differential dependence on glutamine in these different environmental contexts. Further, we show that cystine levels dictate glutamine dependence via the cystine/glutamate antiporter xCT/SLC7A11. Thus, xCT/SLC7A11 expression, in conjunction with environmental cystine, is necessary and sufficient to increase glutamine catabolism, defining important determinants of glutamine anaplerosis and glutaminase dependence in cancer.

Article and author information

Author details

  1. Alexander Muir

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  2. Laura V Danai

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. Dan Y Gui

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  4. Chiara Y Waingarten

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  5. Caroline A Lewis

    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  6. Matthew G Vander Heiden

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    mvh@mit.edu
    Competing interests
    Matthew G Vander Heiden, Is on the scientific advisory board of Agios Pharmaceuticals and Aeglea Biotherapeutics both of which seek to exploit altered metabolism for therapy..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6702-4192

Funding

National Institutes of Health (R01 CA168653)

  • Matthew G Vander Heiden

Howard Hughes Medical Institute (HHMI Faculty Scholar)

  • Matthew G Vander Heiden

Lustgarten Foundation (Research Investigator Award)

  • Matthew G Vander Heiden

Stand Up To Cancer (Innovative Research Grant)

  • Matthew G Vander Heiden

Ludwig Institute for Cancer Research (Ludwig Center at MIT)

  • Matthew G Vander Heiden

National Institutes of Health (R01 CA201276)

  • Matthew G Vander Heiden

National Institutes of Health (P30CA1405141)

  • Matthew G Vander Heiden

National Institutes of Health (F32CA213810)

  • Alexander Muir

National Institutes of Health (F32CA210421)

  • Laura V Danai

National Institutes of Health (T32GM007753)

  • Dan Y Gui

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animals experiments were performed using protocols (#1115-110-18) that were approved by the MIT Committee on Animal Care (IACUC). All surgeries were performed using isoflurane anesthesia administered by vaporizer and every effort was made to minimize suffering.

Reviewing Editor

  1. Ralph DeBerardinis, UT Southwestern Medical Center, United States

Publication history

  1. Received: April 11, 2017
  2. Accepted: August 7, 2017
  3. Accepted Manuscript published: August 15, 2017 (version 1)
  4. Version of Record published: September 7, 2017 (version 2)

Copyright

© 2017, Muir 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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