Cited by 551Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerCancer and biochemical research

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PKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells

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Israelsen, William J., Dayton, Talya L., Davidson, Shawn M., Fiske, Brian P., Hosios, Aaron M., Bellinger, Gary, Li, Jie, Yu, Yimin, Sasaki, Mika, Horner, James W., Burga, Laura N., Xie, Jianxin, Jurczak, Michael J., DePinho, Ronald A., Clish, Clary B., Jacks, Tyler, Kibbey, Richard G., Wulf, Gerburg M., Di Vizio, Dolores, Mills, Gordon B., Cantley, Lewis C., Vander Heiden, Matthew G.·2013·Cell

DOI 10.1016/j.cell.2013.09.025PMC PMC3850755

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Abstract

The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells.

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Authors: Israelsen, W. J., Dayton, T. L., Davidson, S. M., Fiske, B. P., Hosios, A. M., Bellinger, G., Li, J., Yu, Y., Sasaki, M., Horner, J. W., Burga, L. N., Xie, J., Jurczak, M. J., DePinho, R. A., Clish, C. B., Jacks, T., Kibbey, R. G., Wulf, G. M., Di Vizio, D., Mills, G. B., Cantley, L. C., & Vander Heiden, M. G.
Affiliations: Koch Institute for Integrative Cancer Research At MIT (US)
The University of Texas MD Anderson Cancer Center (US)
Beth Israel Deaconess Medical Center (US)
Dana-Farber Cancer Institute (US)
Cell Signaling Technology (United States) (US)
Yale University (US)
Broad Institute (US)
ORCID: Israelsen, William J.
Dayton, Talya L.
Davidson, Shawn M.
Fiske, Brian P.
Hosios, Aaron M.
Li, Jie
Yu, Yimin
Sasaki, Mika
Burga, Laura N.
Xie, Jianxin
Jurczak, Michael J.
DePinho, Ronald A.
Clish, Clary B.
Jacks, Tyler
Kibbey, Richard G.
Wulf, Gerburg M.
Mills, Gordon B.
Cantley, Lewis C.
Venue: Cell
Publisher: Elsevier BV
Published: 2013-10
Volume: 155
Issue: 2
Pages: 397-409
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2013.09.025
PMC: PMC3850755
OpenAlex: W1975215468
Cited by: 549
References: 48
Citations by year: 2026: 25 · 2025: 35 · 2024: 46 · 2023: 32 · 2022: 56 · 2021: 56 · 2020: 43 · 2019: 41 · 2018: 41 · 2017: 44 · 2016: 32 · 2015: 41 · 2014: 50 · 2013: 5
FWCI: 14.99
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
PMC
Funders: Damon Runyon Cancer Research Foundation
Richard and Susan Smith Family Foundation
Agios Pharmaceuticals
National Institutes of Health (DK059635)
National Cancer Institute (5-P30-CA14051, P50CA098258, K08CA136983, R01CA168653, R00CA131472, P30CA014051, P01CA117969, P30CA147882)
National Institute of General Medical Sciences (R01GM056203)
National Institute of Diabetes and Digestive and Kidney Diseases (U24DK059635, R01DK092606, DK059635)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
Keywords: PKM2, PKM1, tumor cell proliferation, mammary tumor formation, BRCA1, breast cancer, cancer metabolism, conditional knockout mice, tumor heterogeneity, anabolic metabolism
MeSH terms: Animals, Base Sequence, Breast Neoplasms, Exons, Female, Humans, Isoenzymes, Mammary Neoplasms, Experimental, Mice, Inbred C57BL, Models, Molecular, Molecular Sequence Data, Mutation, Neoplasm Metastasis, Neoplasm Transplantation, Pyruvate Kinase, RNA Splicing, Mutagenesis, Gene Deletion, Mice, Gene Knockout Techniques, Heterografts

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PKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells

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