Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

By D. Anastasiou, Yimin Yu, William J. Israelsen, Jian-Kang Jiang, M. Boxer, B. Hong, W. Tempel, S. Dimov, M. Shen, Abhishek K. Jha and 33 more. Nature Chemical Biology, 2012

775 citations recorded by the source corpus.

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. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases 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 inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site 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.

Subfields: Biochemistry, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/73fdd0d7ac12e636d4f82e1a090e73b3c6c53466

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In Biochemistry

1. Russell G. Jones
2. Jason W. Locasale
3. Erika L. Pearce
4. M. V. Vander Heiden
5. J. Rathmell
6. Luke A. O'Neill

In Cancer Research

1. Erika L. Pearce
2. Huafeng Zhang
3. Jason W. Locasale
4. M. V. Vander Heiden
5. D. Y. Gui
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7. Alba Luengo
8. Russell G. Jones

In Molecular Biology

1. Erika L. Pearce
2. M. V. Vander Heiden
3. Huafeng Zhang
4. Jason W. Locasale
5. Zhaoyong Li
6. D. Y. Gui
7. Alba Luengo
8. Russell G. Jones

Citations in the corpus

• 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, positive): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript active PKM2 tetramers thereby boosting PKM2 enzymatic activity and limiting tumor growth in vivo (Anastasiou et al., 2012).”
• Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “nists increases PEP-to-pyruvate conversion, reducing the flux of glycolytic intermediates toward anabolic pathways and slowing tumor cell growth (56, 60).”
• Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “Two small molecules, TEPP-46 and DASA-58, can specifically activate PKM2 in cells by promoting PKM2 tetramer formation and preventing inhibition by phosphotyrosine signaling, alter metabolism in cultured cells, and inhibit xenograft tumor growth [141].”
• Targeting Metabolism for Cancer Therapy (2017, background): “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.”
• Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses (2015, background): “Additionally, treating TH1 CD4+ T cells with PKM2activatorDASS,whichwill decrease intracellularPEP levels (data not shown) (Anastasiou et al., 2012), similarly suppressed the production of IFNg and CD40L (Figure S5C).”