Aspartate is an endogenous metabolic limitation for tumour growth
Defining the metabolic limitations of tumour growth will help to develop cancer therapies 1 . Cancer cells proliferate slower in tumours than in standard culture conditions, indicating that a metabolic limitation may restrict cell proliferation in vivo. Aspartate synthesis can limit cancer cell prol...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2020
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| Online Access: | https://hdl.handle.net/1721.1/124932 |
| _version_ | 1826218074814021632 |
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| author | Sullivan, Lucas B. Luengo, Alba Danai, Laura V. Bush, Lauren N. Diehl, Frances F. Hosios, Aaron M. Lau, Allison N. Elmiligy, Sarah Lewis, Caroline A. Vander Heiden, Matthew G. |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Sullivan, Lucas B. Luengo, Alba Danai, Laura V. Bush, Lauren N. Diehl, Frances F. Hosios, Aaron M. Lau, Allison N. Elmiligy, Sarah Lewis, Caroline A. Vander Heiden, Matthew G. |
| author_sort | Sullivan, Lucas B. |
| collection | MIT |
| description | Defining the metabolic limitations of tumour growth will help to develop cancer therapies 1 . Cancer cells proliferate slower in tumours than in standard culture conditions, indicating that a metabolic limitation may restrict cell proliferation in vivo. Aspartate synthesis can limit cancer cell proliferation when respiration is impaired 2-4 ; however, whether acquiring aspartate is endogenously limiting for tumour growth is unknown. We confirm that aspartate has poor cell permeability, which prevents environmental acquisition, whereas the related amino acid asparagine is available to cells in tumours, but cancer cells lack asparaginase activity to convert asparagine to aspartate. Heterologous expression of guinea pig asparaginase 1 (gpASNase1), an enzyme that produces aspartate from asparagine 5 , confers the ability to use asparagine to supply intracellular aspartate to cancer cells in vivo. Tumours expressing gpASNase1 grow at a faster rate, indicating that aspartate acquisition is an endogenous metabolic limitation for the growth of some tumours. Tumours expressing gpASNase1 are also refractory to the growth suppressive effects of metformin, suggesting that metformin inhibits tumour growth by depleting aspartate. These findings suggest that therapeutic aspartate suppression could be effective to treat cancer. |
| first_indexed | 2024-09-23T17:13:45Z |
| format | Article |
| id | mit-1721.1/124932 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T17:13:45Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1249322022-10-03T11:15:36Z Aspartate is an endogenous metabolic limitation for tumour growth Sullivan, Lucas B. Luengo, Alba Danai, Laura V. Bush, Lauren N. Diehl, Frances F. Hosios, Aaron M. Lau, Allison N. Elmiligy, Sarah Lewis, Caroline A. Vander Heiden, Matthew G. Whitehead Institute for Biomedical Research Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Cell Biology Defining the metabolic limitations of tumour growth will help to develop cancer therapies 1 . Cancer cells proliferate slower in tumours than in standard culture conditions, indicating that a metabolic limitation may restrict cell proliferation in vivo. Aspartate synthesis can limit cancer cell proliferation when respiration is impaired 2-4 ; however, whether acquiring aspartate is endogenously limiting for tumour growth is unknown. We confirm that aspartate has poor cell permeability, which prevents environmental acquisition, whereas the related amino acid asparagine is available to cells in tumours, but cancer cells lack asparaginase activity to convert asparagine to aspartate. Heterologous expression of guinea pig asparaginase 1 (gpASNase1), an enzyme that produces aspartate from asparagine 5 , confers the ability to use asparagine to supply intracellular aspartate to cancer cells in vivo. Tumours expressing gpASNase1 grow at a faster rate, indicating that aspartate acquisition is an endogenous metabolic limitation for the growth of some tumours. Tumours expressing gpASNase1 are also refractory to the growth suppressive effects of metformin, suggesting that metformin inhibits tumour growth by depleting aspartate. These findings suggest that therapeutic aspartate suppression could be effective to treat cancer. American Cancer Society. Post-Doctoral Fellowship (PF-15-096-01-TBE) National Institutes of Health (U.S.). Pathway to Independence Award (K99CA218679) Nation al Science Foundation (U.S.) (Grant GRFP DGE-1122374) National Institutes of Health (U.S.). Ruth Kirschstein Fellowship (F32CA210421) Damon Runyon Cancer Research Foundation. Robert Black Fellow ( DRG-2241-15) National Institutes of Health (U.S.) (Grant R01CA201276) National Institutes of Health (U.S.) (Grant R01CA168653) National Institutes of Health (U.S.) (Grant P30CA14051) 2020-04-30T13:00:27Z 2020-04-30T13:00:27Z 2018-06-25 2020-01-30T18:37:06Z Article http://purl.org/eprint/type/JournalArticle 1465-7392 1476-4679 https://hdl.handle.net/1721.1/124932 Sullivan, Lucas B. et al. “Aspartate is an endogenous metabolic limitatio for tumour growth.” Nature cell biology 20 (2018): 782-788 © 2018 The Author(s) en 10.1038/s41556-018-0125-0 Nature cell biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Cell Biology Sullivan, Lucas B. Luengo, Alba Danai, Laura V. Bush, Lauren N. Diehl, Frances F. Hosios, Aaron M. Lau, Allison N. Elmiligy, Sarah Lewis, Caroline A. Vander Heiden, Matthew G. Aspartate is an endogenous metabolic limitation for tumour growth |
| title | Aspartate is an endogenous metabolic limitation for tumour growth |
| title_full | Aspartate is an endogenous metabolic limitation for tumour growth |
| title_fullStr | Aspartate is an endogenous metabolic limitation for tumour growth |
| title_full_unstemmed | Aspartate is an endogenous metabolic limitation for tumour growth |
| title_short | Aspartate is an endogenous metabolic limitation for tumour growth |
| title_sort | aspartate is an endogenous metabolic limitation for tumour growth |
| topic | Cell Biology |
| url | https://hdl.handle.net/1721.1/124932 |
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