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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xc− may constitute a therapeutic target in triple-negative breast carcinoma.
“implying that xc− may constitute a therapeutic target in this setting [553, 554].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [554]
The pronounced addiction of triple-negative breast carcinoma to glutamine relates at least in part to its ability to drive cystine uptake via xc−.
“the pronounced addiction of triple-negative breast carcinoma to glutamine relates (at least in part) to its ability to drive cystine uptake via xc−, implying that xc− may constitute a therapeutic target in this setting [553, 554].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [554]
Extracellular nutrient availability can influence cancer cell dependence on glutamine metabolism.
“However, environmental factors may also come into play, as for instance, the availability of extracellular as discussed below, can influence the dependence of cancer cells on glutamine metabolism73.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [73]
Glutamine is a direct fuel for glutathione as a source of glutamate and is indirectly responsible for cystine uptake via the xCT antiporter system, which takes up cystine and simultaneously secretes glutamate.
“As shown in Fig. 3, glutamine is a direct fuel for the use of glutathione as a source of glutamate and is indirectly responsible for cystine uptake via the xCT antiporter system, which takes up cystine and simultaneously secretes glutamate61.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [61]
Sensitivity to GLS inhibition in vitro is not always consistent in vivo and is dependent on extracellular cystine levels.
“However, sensitivity to GLS inhibition in vitro is not always consistent in vivo, and is dependent on extracellular cystine levels.40”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [40]
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Self-citationMetabolic pathway analysis using stable isotopes in patients with cancer
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Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis
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Self-citation
- 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
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-08-15
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5589418
- 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
- gold
- doi.org
- Licence
- 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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