The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Berman, H. M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.235 · Cited by 40,196
[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 29,915
Colowick, S. P., Joshi, M. D., Jagannathan, & KAPLAN, N. O. (1966) · Cited by 26,137
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
Self-citationRefinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,796
Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?
Trachootham, D., Alexandre, J., & Huang, P. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2803 · Cited by 5,452
PRODRG: a tool for high-throughput crystallography of protein–ligand complexes
Schüttelkopf, A. W., & van Aalten, D. M. F. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904011679 · Cited by 4,837
Regulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06734 · Cited by 2,820
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Items 801–830 of 830
Mei, M., Miao, Q., Li, M. T., Wang, H., Ding, J., Hu, G., & Wei, Y. (2026) · CNS Neuroscience & Therapeutics · doi:10.1002/cns.70968
Ye, P., Li, Z., Cui, X., Wu, H., & Jiang, H. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1852019
Zhang, F., Liu, F., Qin, L., Chen, Y., Ding, M., Cai, S., Di, L., & Zhang, W. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118208
PUF60 is a Critical Regulator of PKM Splicing During Myogenesis
Masaki, S., Nojima, T., Oshiro-Ideue, T., Suenaga, A., Takeuchi, A., Kii, I., Suzuki, K., Tanaka, S., Hagiwara, M., & Kataoka, N. (2026) · Molecular and Cellular Biology · doi:10.1080/10985549.2026.2699151
Pyruvate kinase M2 is elevated in systemic sclerosis and plays a role in its pathogenesis
Steadman, T., & O’Reilly, S. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1827119
Yu, W., Sun, R., Lu, X., Deng, Q., Zhang, H., Chen, S., Dai, S., Hu, T., Li, X., Yang, Y., et al. (2026) · Science Immunology · doi:10.1126/sciimmunol.aeb7315
Serine determines tissue targeted efficacy of PKM2 modulators in atopic dermatitisPreprint
O'Neill, L. A. J., Ashton, T., Broc, S., Davies, G., Domville, M., Makrecka‐Kuka, M., Patel, H., Fenton-May, A. E., Bennett, N. J., Herman, K., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-9496359/v1
Dermawan, D., & Alotaiq, N. (2026) · PLoS ONE · doi:10.1371/journal.pone.0352669
Plumbagin Is a PKM2 Activator That Modulates Glutamine Metabolism and Dependency in Leukemia
Vrdoljak, N., Minden, M. D., & Spagnuolo, P. A. (2026) · Metabolites · doi:10.3390/metabo16080577
Targeting PKM2 Enhances the Anti-Tumor Function of CD8+ T Cells Through Metabolic Reprogramming
Zhang, J., Wu, S., Yin, Q., Liu, Y., Zheng, S., & Yang, P. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27177664
Banerjee, T., & Bose, K. (2026) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2026.101948
Chemoproteomics in covalent cancer drug discovery
Ong, J.-P., Dalziel, M., Johns, D., Zhu, J., & Bertoldo, J. B. (2026) · Drug Discovery Today · doi:10.1016/j.drudis.2026.104817
Miao, C., Wang, Z., Li, K., Lin, J., Wu, X., Zhu, Z., Zhang, X., Zhou, X., Zou, J., Zhu, Y., et al. (2026) · Journal of Molecular Biology · doi:10.1016/j.jmb.2026.170041
Wang, B., Tang, Y., Li, N., Dai, X., Wu, J., Xue, B., Chen, Y., Zhang, J., Kong, L., Li, C., et al. (2026) · Advanced Science · doi:10.1002/advs.77875
Nie, K., Gao, X., Liu, M., You, D., Weng, M., Zheng, T., Lin, J., Rao, S., Zhuo, Y., Wan, J., et al. (2026) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.71404
Shen, J., Yan, F., Yang, S., Yang, K., Liu, C., Jia, X., Fu, X., Xu, M., Zhong, X., Lu, S., et al. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.117567
BindingDB (2023) · UC San Diego · doi:10.7270/q2m330sp
BindingDB (2016) · UC San Diego · doi:10.7270/q25q4xv9
BindingDB (2023) · UC San Diego · doi:10.7270/q2vx0mj9
BindingDB (2016) · UC San Diego · doi:10.7270/q2h70dn5
Marini, A. (2014) · UnissResearch (Università degli Studi di Sassari)
Metabolic Adaptation in Reprogrammed Cancer Cells
Marks, K. M., & Kung, C. K.-H. (2014) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-1-4614-9545-1_7
Self-citation
Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
