Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition
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elife-27713-v2.pdf
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Author(s)
Lewis, Caroline A
Muir, Alexander
Danai, Laura V
Gui, Dan Yi
Waingarten, Chiara Y.
Vander Heiden, Matthew G.
Date Issued
August 2017
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Muir, Alexander et al. “Environmental Cystine Drives Glutamine Anaplerosis and Sensitizes Cancer Cells to Glutaminase Inhibition.” eLife 2017, 6 (August 2017): e27713 © Muir et al
Version
Final published version
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.7554/eLife.27713
