Metabolic Pathway Alterations that Support Cell Proliferation
Proliferating cells adapt metabolism to support the conversion of available nutrients into biomass. How cell metabolism is regulated to balance the production of ATP, metabolite building blocks, and reducing equivalents remains uncertain. Proliferative metabolism often involves an increased rate of...
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| Language: | en_US |
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Cold Spring Harbor Laboratory Press
2013
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| Online Access: | http://hdl.handle.net/1721.1/76317 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0003-0046-1360 https://orcid.org/0000-0001-6909-4568 https://orcid.org/0000-0002-7994-7963 |
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| author | Vander Heiden, Matthew G. Lunt, Sophia Yunkyungkwon Dayton, Talya Lucia Fiske, Brian Prescott Israelsen, William James Mattaini, Katherine Ruth Vokes, N. I. Stephanopoulos, G. Cantley, Lewis C. Metallo, Christian M. Locasale, Jason W. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Vander Heiden, Matthew G. Lunt, Sophia Yunkyungkwon Dayton, Talya Lucia Fiske, Brian Prescott Israelsen, William James Mattaini, Katherine Ruth Vokes, N. I. Stephanopoulos, G. Cantley, Lewis C. Metallo, Christian M. Locasale, Jason W. |
| author_sort | Vander Heiden, Matthew G. |
| collection | MIT |
| description | Proliferating cells adapt metabolism to support the conversion of available nutrients into biomass. How cell metabolism is regulated to balance the production of ATP, metabolite building blocks, and reducing equivalents remains uncertain. Proliferative metabolism often involves an increased rate of glycolysis. A key regulated step in glycolysis is catalyzed by pyruvate kinase to convert phosphoenolpyruvate (PEP) to pyruvate. Surprisingly, there is strong selection for expression of the less active M2 isoform of pyruvate kinase (PKM2) in tumors and other proliferative tissues. Cell growth signals further decrease PKM2 activity, and cells with less active PKM2 use another pathway with separate regulatory properties to convert PEP to pyruvate. One consequence of using this alternative pathway is an accumulation of 3-phosphoglycerate (3PG) that leads to the diversion of 3PG into the serine biosynthesis pathway. In fact, in some cancers a substantial portion of the total glucose flux is directed toward serine synthesis, and genetic evidence suggests that glucose flux into this pathway can promote cell transformation. Environmental conditions can also influence the pathways that cells use to generate biomass with the source of carbon for lipid synthesis changing based on oxygen availability. Together, these findings argue that distinct metabolic phenotypes exist among proliferating cells, and both genetic and environmental factors influence how metabolism is regulated to support cell growth. |
| first_indexed | 2024-09-23T10:02:50Z |
| format | Article |
| id | mit-1721.1/76317 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:02:50Z |
| publishDate | 2013 |
| publisher | Cold Spring Harbor Laboratory Press |
| record_format | dspace |
| spelling | mit-1721.1/763172022-09-30T18:33:05Z Metabolic Pathway Alterations that Support Cell Proliferation Vander Heiden, Matthew G. Lunt, Sophia Yunkyungkwon Dayton, Talya Lucia Fiske, Brian Prescott Israelsen, William James Mattaini, Katherine Ruth Vokes, N. I. Stephanopoulos, G. Cantley, Lewis C. Metallo, Christian M. Locasale, Jason W. Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Vander Heiden, Matthew G. Vander Heiden, Matthew G. Lunt, Sophia Yunkyungkwon Dayton, Talya Lucia Fiske, Brian Prescott Israelsen, William James Mattaini, Katherine Ruth Vokes, N. I. Stephanopoulos, G. Metallo, Christian M. Proliferating cells adapt metabolism to support the conversion of available nutrients into biomass. How cell metabolism is regulated to balance the production of ATP, metabolite building blocks, and reducing equivalents remains uncertain. Proliferative metabolism often involves an increased rate of glycolysis. A key regulated step in glycolysis is catalyzed by pyruvate kinase to convert phosphoenolpyruvate (PEP) to pyruvate. Surprisingly, there is strong selection for expression of the less active M2 isoform of pyruvate kinase (PKM2) in tumors and other proliferative tissues. Cell growth signals further decrease PKM2 activity, and cells with less active PKM2 use another pathway with separate regulatory properties to convert PEP to pyruvate. One consequence of using this alternative pathway is an accumulation of 3-phosphoglycerate (3PG) that leads to the diversion of 3PG into the serine biosynthesis pathway. In fact, in some cancers a substantial portion of the total glucose flux is directed toward serine synthesis, and genetic evidence suggests that glucose flux into this pathway can promote cell transformation. Environmental conditions can also influence the pathways that cells use to generate biomass with the source of carbon for lipid synthesis changing based on oxygen availability. Together, these findings argue that distinct metabolic phenotypes exist among proliferating cells, and both genetic and environmental factors influence how metabolism is regulated to support cell growth. Burroughs Wellcome Fund Damon Runyon Cancer Research Foundation Smith Family Foundation Starr Cancer Consortium National Institutes of Health (U.S.) 2013-01-18T20:27:58Z 2013-01-18T20:27:58Z 2012-01 Article http://purl.org/eprint/type/JournalArticle 0091-7451 1943-4456 http://hdl.handle.net/1721.1/76317 Vander Heiden, M. G. et al. “Metabolic Pathway Alterations That Support Cell Proliferation.” Cold Spring Harbor Symposia on Quantitative Biology 76.0 (2012): 325–334. Web. https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0003-0046-1360 https://orcid.org/0000-0001-6909-4568 https://orcid.org/0000-0002-7994-7963 en_US http://dx.doi.org/10.1101/sqb.2012.76.010900 Cold Spring Harbor Symposia on Quantitative Biology Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Cold Spring Harbor Laboratory Press Vander Heiden via Courtney Crummett |
| spellingShingle | Vander Heiden, Matthew G. Lunt, Sophia Yunkyungkwon Dayton, Talya Lucia Fiske, Brian Prescott Israelsen, William James Mattaini, Katherine Ruth Vokes, N. I. Stephanopoulos, G. Cantley, Lewis C. Metallo, Christian M. Locasale, Jason W. Metabolic Pathway Alterations that Support Cell Proliferation |
| title | Metabolic Pathway Alterations that Support Cell Proliferation |
| title_full | Metabolic Pathway Alterations that Support Cell Proliferation |
| title_fullStr | Metabolic Pathway Alterations that Support Cell Proliferation |
| title_full_unstemmed | Metabolic Pathway Alterations that Support Cell Proliferation |
| title_short | Metabolic Pathway Alterations that Support Cell Proliferation |
| title_sort | metabolic pathway alterations that support cell proliferation |
| url | http://hdl.handle.net/1721.1/76317 https://orcid.org/0000-0002-6702-4192 https://orcid.org/0000-0003-0046-1360 https://orcid.org/0000-0001-6909-4568 https://orcid.org/0000-0002-7994-7963 |
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