Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition
- Massachusetts Institute of Technology, United States
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.
Data availability
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SNP and Expression data from the Cancer Cell Line Encyclopedia (CCLE)Publicly available at the NCBI Gene Expression Omnibus (accession no. GSE36139).
Article and author information
Author details
Matthew G Vander Heiden
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.
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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Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition
eLife 6:e27713.
https://doi.org/10.7554/eLife.27713
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