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Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma
BACKGROUND: Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of the glycolytic enzyme pyruvate kinase. PKM2 expression is associated with embryogenesis, tissue regeneration, and cancer. PKM2 is also the pyruvate kinase isoform expressed in most wild-type adult tissue...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977456/ https://www.ncbi.nlm.nih.gov/pubmed/29854399 http://dx.doi.org/10.1186/s40170-018-0179-2 |
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author | Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn M. Bhutkar, Arjun Lewis, Caroline A. Bronson, Roderick T. Vander Heiden, Matthew G. Jacks, Tyler |
author_facet | Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn M. Bhutkar, Arjun Lewis, Caroline A. Bronson, Roderick T. Vander Heiden, Matthew G. Jacks, Tyler |
author_sort | Dayton, Talya L. |
collection | PubMed |
description | BACKGROUND: Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of the glycolytic enzyme pyruvate kinase. PKM2 expression is associated with embryogenesis, tissue regeneration, and cancer. PKM2 is also the pyruvate kinase isoform expressed in most wild-type adult tissues, with PKM1 restricted primarily to skeletal muscle, heart, and brain. To interrogate the functional requirement for PKM2 during tumor initiation in an autochthonous mouse model for soft tissue sarcoma (STS), we used a conditional Pkm2 allele (Pkm2(fl)) to abolish PKM2 expression. RESULTS: PKM2 deletion slowed tumor onset but did not abrogate eventual tumor outgrowth. PKM2-null sarcoma cells expressed PKM1 with tumors containing a high number of infiltrating PKM2 expressing stromal cells. End-stage PKM2-null tumors showed increased proliferation compared to tumors with a wild-type Pkm2 allele, and tumor metabolite analysis revealed metabolic changes associated with PKM2 loss. CONCLUSIONS: While PKM2 is not required for soft tissue sarcoma growth, PKM2 expression may facilitate initiation of this tumor type. Because these data differ from what has been observed in other cancer models where PKM2 has been deleted, they argue that the consequences of PKM2 loss during tumor initiation are dependent on the tumor type. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40170-018-0179-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5977456 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-59774562018-05-31 Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn M. Bhutkar, Arjun Lewis, Caroline A. Bronson, Roderick T. Vander Heiden, Matthew G. Jacks, Tyler Cancer Metab Research BACKGROUND: Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of the glycolytic enzyme pyruvate kinase. PKM2 expression is associated with embryogenesis, tissue regeneration, and cancer. PKM2 is also the pyruvate kinase isoform expressed in most wild-type adult tissues, with PKM1 restricted primarily to skeletal muscle, heart, and brain. To interrogate the functional requirement for PKM2 during tumor initiation in an autochthonous mouse model for soft tissue sarcoma (STS), we used a conditional Pkm2 allele (Pkm2(fl)) to abolish PKM2 expression. RESULTS: PKM2 deletion slowed tumor onset but did not abrogate eventual tumor outgrowth. PKM2-null sarcoma cells expressed PKM1 with tumors containing a high number of infiltrating PKM2 expressing stromal cells. End-stage PKM2-null tumors showed increased proliferation compared to tumors with a wild-type Pkm2 allele, and tumor metabolite analysis revealed metabolic changes associated with PKM2 loss. CONCLUSIONS: While PKM2 is not required for soft tissue sarcoma growth, PKM2 expression may facilitate initiation of this tumor type. Because these data differ from what has been observed in other cancer models where PKM2 has been deleted, they argue that the consequences of PKM2 loss during tumor initiation are dependent on the tumor type. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40170-018-0179-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-05-31 /pmc/articles/PMC5977456/ /pubmed/29854399 http://dx.doi.org/10.1186/s40170-018-0179-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Dayton, Talya L. Gocheva, Vasilena Miller, Kathryn M. Bhutkar, Arjun Lewis, Caroline A. Bronson, Roderick T. Vander Heiden, Matthew G. Jacks, Tyler Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
title | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
title_full | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
title_fullStr | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
title_full_unstemmed | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
title_short | Isoform-specific deletion of PKM2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
title_sort | isoform-specific deletion of pkm2 constrains tumor initiation in a mouse model of soft tissue sarcoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977456/ https://www.ncbi.nlm.nih.gov/pubmed/29854399 http://dx.doi.org/10.1186/s40170-018-0179-2 |
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