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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| Format: | Article |
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eLife Sciences Publications, Ltd
2018
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| Online Access: | http://hdl.handle.net/1721.1/113571 https://orcid.org/0000-0002-8206-8003 https://orcid.org/0000-0003-0130-3428 https://orcid.org/0000-0002-6702-4192 |
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| author | Lewis, Caroline A Muir, Alexander Danai, Laura V Gui, Dan Yi Waingarten, Chiara Y. Vander Heiden, Matthew G. |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Lewis, Caroline A Muir, Alexander Danai, Laura V Gui, Dan Yi Waingarten, Chiara Y. Vander Heiden, Matthew G. |
| author_sort | Lewis, Caroline A |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:17:11Z |
| format | Article |
| id | mit-1721.1/113571 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:17:11Z |
| publishDate | 2018 |
| publisher | eLife Sciences Publications, Ltd |
| record_format | dspace |
| spelling | mit-1721.1/1135712022-09-26T16:59:21Z Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition Lewis, Caroline A Muir, Alexander Danai, Laura V Gui, Dan Yi Waingarten, Chiara Y. Vander Heiden, Matthew G. Koch Institute for Integrative Cancer Research at MIT Muir, Alexander Danai, Laura V Gui, Dan Yi Waingarten, Chiara Y. Vander Heiden, Matthew G. 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. National Institutes of Health (U.S.) (Grant R01CA168653) National Institutes of Health (U.S.) (Grant R01CA201276) National Institutes of Health (U.S.) (Grant P30CA1405141) National Institutes of Health (U.S.) (Award F32CA213810) National Institutes of Health (U.S.) (Award F32CA210421) 2018-02-12T15:55:40Z 2018-02-12T15:55:40Z 2017-08 2017-04 2018-02-02T18:54:20Z Article http://purl.org/eprint/type/JournalArticle 2050-084X http://hdl.handle.net/1721.1/113571 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 https://orcid.org/0000-0002-8206-8003 https://orcid.org/0000-0003-0130-3428 https://orcid.org/0000-0002-6702-4192 http://dx.doi.org/10.7554/eLife.27713 eLife Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd eLife |
| spellingShingle | Lewis, Caroline A Muir, Alexander Danai, Laura V Gui, Dan Yi Waingarten, Chiara Y. Vander Heiden, Matthew G. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition |
| title | Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition |
| title_full | Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition |
| title_fullStr | Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition |
| title_full_unstemmed | Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition |
| title_short | Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition |
| title_sort | environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition |
| url | http://hdl.handle.net/1721.1/113571 https://orcid.org/0000-0002-8206-8003 https://orcid.org/0000-0003-0130-3428 https://orcid.org/0000-0002-6702-4192 |
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