PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells
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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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Pyruvate kinase expression is dispensable for the growth of some tumors.
“but because pyruvate kinase expression is dispensable for the growth of some tumors (Cortes-Cros et al., 2013; Israelsen et al., 2013), whether pyruvate kinase activation will lead to durable responses remains an area of active study”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Israelsen et al., 2013
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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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 155
- Issue
- 2
- Pages
- 397-409
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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