Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer
During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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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/1721.1/114945 https://orcid.org/0000-0002-6702-4192 |
| _version_ | 1826200391564394496 |
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| author | Sayin, Volkan I LeBoeuf, Sarah E Singh, Simranjit X Biancur, Douglas Guzelhan, Betul S Alvarez, Samantha W Wu, Warren L Karakousi, Triantafyllia R Zavitsanou, Anastasia Maria Ubriaco, Julian Karagiannis, Dimitris Morris, Patrick J Thomas, Craig J Possemato, Richard Papagiannakopoulos, Thales Davidson, Shawn M Muir, Alexander Vander Heiden, Matthew G. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Sayin, Volkan I LeBoeuf, Sarah E Singh, Simranjit X Biancur, Douglas Guzelhan, Betul S Alvarez, Samantha W Wu, Warren L Karakousi, Triantafyllia R Zavitsanou, Anastasia Maria Ubriaco, Julian Karagiannis, Dimitris Morris, Patrick J Thomas, Craig J Possemato, Richard Papagiannakopoulos, Thales Davidson, Shawn M Muir, Alexander Vander Heiden, Matthew G. |
| author_sort | Sayin, Volkan I |
| collection | MIT |
| description | During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by xc-antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited. |
| first_indexed | 2024-09-23T11:35:40Z |
| format | Article |
| id | mit-1721.1/114945 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T11:35:40Z |
| publishDate | 2018 |
| publisher | eLife Sciences Publications, Ltd |
| record_format | dspace |
| spelling | mit-1721.1/1149452022-10-01T04:40:04Z Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer Sayin, Volkan I LeBoeuf, Sarah E Singh, Simranjit X Biancur, Douglas Guzelhan, Betul S Alvarez, Samantha W Wu, Warren L Karakousi, Triantafyllia R Zavitsanou, Anastasia Maria Ubriaco, Julian Karagiannis, Dimitris Morris, Patrick J Thomas, Craig J Possemato, Richard Papagiannakopoulos, Thales Davidson, Shawn M Muir, Alexander Vander Heiden, Matthew G. Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Davidson, Shawn M Muir, Alexander Vander Heiden, Matthew G. During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by xc-antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited. 2018-04-24T18:55:54Z 2018-04-24T18:55:54Z 2017-10 2017-04 2018-04-20T19:04:09Z Article http://purl.org/eprint/type/JournalArticle 2050-084X http://hdl.handle.net/1721.1/114945 Sayin, Volkan I, Sarah E LeBoeuf, Simranjit X Singh, Shawn M Davidson, Douglas Biancur, Betul S Guzelhan, Samantha W Alvarez, et al. “Activation of the NRF2 Antioxidant Program Generates an Imbalance in Central Carbon Metabolism in Cancer.” eLife 6 (October 2017): e28083 https://orcid.org/0000-0002-6702-4192 http://dx.doi.org/10.7554/ELIFE.28083 eLife CC0 1.0 Universal (CC0 1.0) https://creativecommons.org/publicdomain/zero/1.0/ application/pdf eLife Sciences Publications, Ltd eLife |
| spellingShingle | Sayin, Volkan I LeBoeuf, Sarah E Singh, Simranjit X Biancur, Douglas Guzelhan, Betul S Alvarez, Samantha W Wu, Warren L Karakousi, Triantafyllia R Zavitsanou, Anastasia Maria Ubriaco, Julian Karagiannis, Dimitris Morris, Patrick J Thomas, Craig J Possemato, Richard Papagiannakopoulos, Thales Davidson, Shawn M Muir, Alexander Vander Heiden, Matthew G. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer |
| title | Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer |
| title_full | Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer |
| title_fullStr | Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer |
| title_full_unstemmed | Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer |
| title_short | Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer |
| title_sort | activation of the nrf2 antioxidant program generates an imbalance in central carbon metabolism in cancer |
| url | http://hdl.handle.net/1721.1/114945 https://orcid.org/0000-0002-6702-4192 |
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