Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
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Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.
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Activation of pyruvate kinase can inhibit cancer cell proliferation and tumor growth in some settings.
“Indeed, activation of pyruvate kinase can inhibit cancer cell proliferation and tumor growth in some settings (Anastasiou et al., 2012; Kung et al., 2012; Walsh et al., 2010), 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”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Anastasiou et al., 2012
Activating PKM2 with small-molecule agonists increases PEP-to-pyruvate conversion, reduces flux of glycolytic intermediates toward anabolic pathways, and slows tumor cell growth.
“Activating PKM2 by using small-molecule agonists increases PEP-to-pyruvate conversion, reducing the flux of glycolytic intermediates toward anabolic pathways and slowing tumor cell growth (56, 60).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [56]
PKM2 exists as inactive dimer or active tetramer, and oscillation between these states influences ability of cells to maintain anabolic metabolism.
“PKM2 exists as either an inactive dimer or an active tetramer, and oscillation between these two states influences the ability of cells to maintain anabolic metabolism (56).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [56]
TEPP-46 and DASA-58 are highly specific small-molecule PKM2 activators that promote active PKM2 tetramers, boost PKM2 enzymatic activity, and limit tumor growth in vivo.
“In order to examine the functional relevance of PKM2 for LPS action we next examined the effect of two highly specific small-molecule PKM2 activators, TEPP-46 and DASA-58.”
From Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages (2015) · cites this paper as Anastasiou et al., 2012
TEPP-46, but not DASA-58, is pharmacokinetically validated in vivo.
“TEPP-46, but not DASA-58, is pharmacokinetically validated in vivo (Anastasiou et al., 2012).”
From Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages (2015) · cites this paper as Anastasiou et al., 2012
DASA-58 and TEPP-46 are well-characterized and highly specific compounds that bind PKM2, which then forms a tight tetramer with PKM1-like kinetic properties, an event resistant to inhibition by tyrosine phosphorylation.
“These well-characterized and highly specific compounds bind PKM2, which then forms a tight tetramer with PKM1-like kinetic properties, an event that is resistant to inhibition by tyrosine phosphorylation.”
From Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages (2015) · cites this paper as Anastasiou et al., 2012
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“PKM1 is constitutively active, while, PKM2 is subjected to allosteric regulation and can adopt a low or high activity state (Anastasiou et al., 2012).”
BackgroundMetabolomics in cancer research and emerging applications in clinical oncology
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Self-citation
- Authors
- Anastasiou, D., Yu, Y., Israelsen, W. J., Jiang, J.-K., Boxer, M. B., Hong, B. S., Tempel, W., Dimov, S., Shen, M., Jha, A., Yang, H., Mattaini, K. R., Metallo, C. M., Fiske, B. P., Courtney, K. D., Malstrom, S., Khan, T. M., Kung, C., Skoumbourdis, A. P., Veith, H., Southall, N., Walsh, M. J., Brimacombe, K. R., Leister, W., Lunt, S. Y., Johnson, Z. R., Yen, K. E., Kunii, K., Davidson, S. M., Christofk, H. R., Austin, C. P., Inglese, J., Harris, M. H., Asara, J. M., Stephanopoulos, G., Salituro, F. G., Jin, S., Dang, L., Auld, D. S., Park, H.-W., Cantley, L. C., Thomas, C. J., & Vander Heiden, M. G.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Massachusetts Institute of Technology (US)
- National Institutes of Health (US)
- University of Toronto (CA)
- Agios Pharmaceuticals (United States) (US)
- University of California San Diego (US)
- Boston Children's Hospital (US)
- ORCID
- Anastasiou, Dimitrios
- Yu, Yimin
- Israelsen, William J
- Jiang, Jian-Kang
- Tempel, Wolfram
- Shen, Min
- Jha, Abhishek
- Yang, Hua
- Mattaini, Katherine R
- Metallo, Christian M
- Fiske, Brian P
- Courtney, Kevin D
- Khan, Tahsin M
- Southall, Noel
- Walsh, Martin J
- Brimacombe, Kyle R
- Lunt, Sophia Y
- Johnson, Zachary R
- Yen, Katharine E
- Kunii, Kaiko
- Davidson, Shawn M
- Christofk, Heather R
- Austin, Christopher P
- Inglese, James
- Harris, Marian H
- Asara, John M
- Stephanopoulos, Gregory
- Salituro, Francesco G
- Dang, Lenny
- Auld, Douglas S
- Park, Hee-Won
- Cantley, Lewis C
- Thomas, Craig J
- Venue
- Nature Chemical Biology
- Published
- 2012-08-26
- Volume
- 8
- Issue
- 10
- Pages
- 839-847
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3711671
- OpenAlex
- W2125836344
- Cited by
- 816
- References
- 46
- Citations by year
- 2026: 39 · 2025: 76 · 2024: 61 · 2023: 66 · 2022: 59 · 2021: 73 · 2020: 69 · 2019: 47 · 2018: 60 · 2017: 49 · 2016: 53 · 2015: 55 · 2014: 55 · 2013: 45 · 2012: 9
- FWCI
- 17.46
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-11-26)
- Open access
- green
- europepmc.org
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Chicago
- Genome Canada
- Wellcome Trust
- Knut och Alice Wallenbergs Stiftelse
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute of Mental Health (R03MH085679)
- National Cancer Institute (5P30CA1405141, R01CA160458, P01CA120964, P30CA006516)
- National Institute of General Medical Sciences (R01 GM56203, R01GM056203)
- Biological and Environmental Research
- Argonne National Laboratory
- 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 › Biochemical and Molecular Research
- Keywords
- PKM2, tetramerization, fructose-1,6-bisphosphate, small molecule activators, PKM1, tumor growth inhibition, tumor xenografts, cancer metabolism, glucose metabolism, tyrosine phosphorylation, anabolic metabolism, enzyme activation
- MeSH terms
- Animals, Biopolymers, Cell Transformation, Neoplastic, Humans, Neoplasms, Pyruvate Kinase, Blotting, Western, Enzyme Activators, Cell Proliferation, Mice
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