Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition

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 t...

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Bibliographic Details
Published in:eLife 2017-08, Vol.6
Main Authors: Muir, Alexander, Danai, Laura V, Gui, Dan Y, Waingarten, Chiara Y, Lewis, Caroline A, Vander Heiden, Matthew G
Format: Article
Language:English
Subjects:
Amino Acid Transport System y+ - metabolism
Amino acids
Ammonia
Animals
Cancer
Cancer Biology
Cancer cells
Cancer prevention
Carbon
Cattle
Cell culture
Cell Proliferation - drug effects
Cysteine
Cystine
Cystine - pharmacology
environment
Glutaminase
Glutaminase - antagonists & inhibitors
Glutamine
Glutamine - metabolism
Humans
Medical research
Metabolism
Metabolites
Mice, Nude
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Nitrogen
Nutrients
Plasma
SLC7A11
Tissue culture
Tumor cell lines
Tumor Cells, Cultured
Tumor Microenvironment
Tumors
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Summary: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/ . Thus, xCT/ 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.27713