Journal article
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Nature chemical biology, Vol.8(10), pp.839-847
10/01/2012
DOI: 10.1038/NCHEMBIO.1060
PMID: 22922757
Abstract
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.
Details
- Title: Subtitle
- Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
- Creators
- Dimitrios Anastasiou - Beth Israel Deaconess Medical CenterYimin Yu - Massachusetts Institute of TechnologyWilliam J. Israelsen - Massachusetts Institute of TechnologyJian-Kang Jiang - Natl Ctr Adv Translat Sci, NIH, Chem Genom Ctr, Bethesda, MD USAMatthew B. Boxer - National Institutes of HealthBum Soo Hong - University of TorontoWolfram Tempel - University of TorontoSvetoslav Dimov - University of TorontoMin Shen - National Institutes of HealthAbhishek Jha - Massachusetts Institute of TechnologyHua Yang - Agios Pharmaceuticals (United States)Katherine R. Mattaini - Massachusetts Institute of TechnologyChristian M. Metallo - University of California San DiegoBrian P. Fiske - Massachusetts Institute of TechnologyKevin D. Courtney - Beth Israel Deaconess Medical CenterScott Malstrom - Massachusetts Institute of TechnologyTahsin M. Khan - Massachusetts Institute of TechnologyCharles Kung - Agios Pharmaceuticals (United States)Amanda P. Skoumbourdis - National Institutes of HealthHenrike Veith - National Institutes of HealthNoel Southall - National Institutes of HealthMartin J. Walsh - National Institutes of HealthKyle R. Brimacombe - National Institutes of HealthWilliam Leister - National Institutes of HealthSophia Y. Lunt - Massachusetts Institute of TechnologyZachary R. Johnson - Massachusetts Institute of TechnologyKatharine E. Yen - Agios Pharmaceuticals (United States)Kaiko Kunii - Agios Pharmaceuticals (United States)Shawn M. Davidson - Massachusetts Institute of TechnologyHeather R. Christofk - Beth Israel Deaconess Medical CenterChristopher P. Austin - National Institutes of HealthJames Inglese - National Institutes of HealthMarian H. Harris - Boston Children's HospitalJohn M. Asara - Beth Israel Deaconess Medical CenterGregory Stephanopoulos - Massachusetts Institute of TechnologyFrancesco G. Salituro - Agios Pharmaceuticals (United States)Shengfang Jin - Agios Pharmaceuticals (United States)Lenny Dang - Agios Pharmaceuticals (United States)Douglas S. Auld - National Institutes of HealthHee-Won Park - University of TorontoLewis C. Cantley - Beth Israel Deaconess Medical CenterCraig J. Thomas - National Institutes of HealthMatthew G. Vander Heiden - Harvard UniversityArgonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Resource Type
- Journal article
- Publication Details
- Nature chemical biology, Vol.8(10), pp.839-847
- DOI
- 10.1038/NCHEMBIO.1060
- PMID
- 22922757
- NLM abbreviation
- Nat Chem Biol
- ISSN
- 1552-4450
- eISSN
- 1552-4469
- Publisher
- NATURE PORTFOLIO
- Number of pages
- 9
- Grant note
- Wellcome Trust Intramural NIH HHS Howard Hughes Medical Institute R03MH085679; R03 MH085679 / NIMH NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) P01CA120964; P30CA014051; P30CA006516 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) CIHR; Canadian Institutes of Health Research (CIHR) 5P30CA006516; P30 CA006516; R01 CA160458; 5P30CA1405141; P01 CA120964; 5P01CA120964 / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01 GM56203; R01 GM056203 / NIGMS NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 10/01/2012
- Academic Unit
- Surgery
- Record Identifier
- 9985224321802771
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