Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation
The de novo serine synthesis pathway is upregulated in many cancers. However, even cancer cells with increased serine synthesis take up large amounts of serine from the environment1, and we confirm that exogenous serine is needed for maximal proliferation of these cells. Here we show that even when...
| 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/1721.1/127671 |
| _version_ | 1811071001452085248 |
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| author | Diehl, Frances F. Lewis, Caroline A. Fiske, Brian Prescott Vander Heiden, Matthew G. |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Diehl, Frances F. Lewis, Caroline A. Fiske, Brian Prescott Vander Heiden, Matthew G. |
| author_sort | Diehl, Frances F. |
| collection | MIT |
| description | The de novo serine synthesis pathway is upregulated in many cancers. However, even cancer cells with increased serine synthesis take up large amounts of serine from the environment1, and we confirm that exogenous serine is needed for maximal proliferation of these cells. Here we show that even when enzymes in the serine synthesis pathway are genetically upregulated, the demand for oxidized NAD+ constrains serine synthesis, rendering serine-deprived cells sensitive to conditions that decrease the cellular NAD+/NADH ratio. Further, purine depletion is a major consequence of reduced intracellular serine availability, particularly when NAD+ regeneration is impaired. Thus, cells rely on exogenous serine consumption to maintain purine biosynthesis. In support of this explanation, providing exogenous purine nucleobases, or increasing NAD+ availability to facilitate de novo serine and purine synthesis, rescues maximal proliferation even in the absence of extracellular serine. Together, these data indicate that NAD+ is an endogenous limitation for cancer cells to synthesize the serine needed for purine production to support rapid proliferation. |
| first_indexed | 2024-09-23T08:44:34Z |
| format | Article |
| id | mit-1721.1/127671 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:44:34Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1276712022-09-23T14:15:53Z Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation Diehl, Frances F. Lewis, Caroline A. Fiske, Brian Prescott Vander Heiden, Matthew G. Koch Institute for Integrative Cancer Research at MIT The de novo serine synthesis pathway is upregulated in many cancers. However, even cancer cells with increased serine synthesis take up large amounts of serine from the environment1, and we confirm that exogenous serine is needed for maximal proliferation of these cells. Here we show that even when enzymes in the serine synthesis pathway are genetically upregulated, the demand for oxidized NAD+ constrains serine synthesis, rendering serine-deprived cells sensitive to conditions that decrease the cellular NAD+/NADH ratio. Further, purine depletion is a major consequence of reduced intracellular serine availability, particularly when NAD+ regeneration is impaired. Thus, cells rely on exogenous serine consumption to maintain purine biosynthesis. In support of this explanation, providing exogenous purine nucleobases, or increasing NAD+ availability to facilitate de novo serine and purine synthesis, rescues maximal proliferation even in the absence of extracellular serine. Together, these data indicate that NAD+ is an endogenous limitation for cancer cells to synthesize the serine needed for purine production to support rapid proliferation. NIH (Grants F31CA236036, R01CA201276, R01CA168653 and P30CA14051) 2020-09-21T20:01:15Z 2020-09-21T20:01:15Z 2019-09 2020-09-18T18:34:16Z Article http://purl.org/eprint/type/JournalArticle 2522-5812 https://hdl.handle.net/1721.1/127671 Diehl, Frances F. et al. "Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation." Nature Metabolism 1, 9 (September 2019): 861–867 © 2019 The Author(s) en https://dx.doi.org/10.1038/S42255-019-0108-X Nature Metabolism Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Diehl, Frances F. Lewis, Caroline A. Fiske, Brian Prescott Vander Heiden, Matthew G. Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation |
| title | Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation |
| title_full | Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation |
| title_fullStr | Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation |
| title_full_unstemmed | Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation |
| title_short | Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation |
| title_sort | cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation |
| url | https://hdl.handle.net/1721.1/127671 |
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