Cited by 314Cancer, Hypoxia, and MetabolismAmino Acid Enzymes and MetabolismSulfur Compounds in Biology

The DOI matches its Crossref record; 85 of the 85 references it cites were found in a registry or an index.

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

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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.

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Metadata

Authors
Muir, A., Danai, L. V., Gui, D. Y., Waingarten, C. Y., Lewis, C. A., & Vander Heiden, M. G.
Affiliations
  • Koch Institute for Integrative Cancer Research At MIT (US)
  • Whitehead Institute for Biomedical Research (US)
  • Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
Venue
eLife
Published
2017-08-15
Volume
6
ISSN
2050-084X (ISSN-L)
OpenAlex
W2606822414
Cited by
311
References
85
Citations by year
2026: 19 · 2025: 26 · 2024: 37 · 2023: 36 · 2022: 29 · 2021: 39 · 2020: 52 · 2019: 42 · 2018: 22 · 2017: 8
FWCI
11.39
Type
journal article
Language
en
Open access
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders
  • National Institutes of Health (R01 CA168653, R01 CA201276, P30CA1405141, F32CA213810, F32CA210421, T32GM007753)
  • Lustgarten Foundation (Research Investigator Award)
  • Stand Up To Cancer (Innovative Research Grant)
  • Ludwig Institute for Cancer Research (Ludwig Center at MIT)
  • Howard Hughes Medical Institute (HHMI Faculty Scholar)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
Keywords
cystine, glutamine anaplerosis, glutaminase inhibition, SLC7A11, glutamine catabolism, TCA cycle, cancer metabolism, bovine serum, culture medium composition, glutamine addiction
MeSH terms
Animals, Cattle, Cystine, Glutaminase, Glutamine, Humans, Mice, Nude, Neoplasms, Tumor Cells, Cultured, Amino Acid Transport System y+, Cell Proliferation, Tumor Microenvironment

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