Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Dimitrios Anastasiou, Yimin Yu, William J. Israelsen, Jian Kang Jiang, Matthew B. Boxer, Bum Soo Hong, Wolfram Tempel, Svetoslav Dimov, Min Shen, Abhishek Jha, Hua Yang, Katherine R. Mattaini, Christian M. Metallo, Brian P. Fiske, Kevin D. Courtney, Scott Malstrom, Tahsin M. Khan, Charles Kung, Amanda P. Skoumbourdis, Henrike Veith & 23 others Noel Southall, Martin J. Walsh, Kyle R. Brimacombe, William Leister, Sophia Y. Lunt, Zachary R. Johnson, Katharine E. Yen, Kaiko Kunii, Shawn M. Davidson, Heather R. Christofk, Christopher P. Austin, James Inglese, Marian H. Harris, John M. Asara, Gregory Stephanopoulos, Francesco G. Salituro, Shengfang Jin, Lenny Dang, Douglas S. Auld, Hee Won Park, Lewis C. Cantley, Craig J. Thomas, Matthew G. Vander Heiden

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)839-847
Number of pages9
JournalNature Chemical Biology
Volume8
Issue number10
DOIs
StatePublished - 2012
Externally publishedYes

Profile

Pyruvate Kinase
Carcinogenesis
Neoplasms
Fructose
Cell Proliferation
Enzymes
Proteins
Phosphotyrosine
Heterografts
Tyrosine
Protein Isoforms
Glucose

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Anastasiou, D., Yu, Y., Israelsen, W. J., Jiang, J. K., Boxer, M. B., Hong, B. S., ... Vander Heiden, M. G. (2012). Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nature Chemical Biology, 8(10), 839-847. DOI: 10.1038/nchembio.1060

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. / Anastasiou, Dimitrios; Yu, Yimin; Israelsen, William J.; Jiang, Jian Kang; Boxer, Matthew B.; Hong, Bum Soo; Tempel, Wolfram; Dimov, Svetoslav; Shen, Min; Jha, Abhishek; Yang, Hua; Mattaini, Katherine R.; Metallo, Christian M.; Fiske, Brian P.; Courtney, Kevin D.; Malstrom, Scott; Khan, Tahsin M.; Kung, Charles; Skoumbourdis, Amanda P.; Veith, Henrike; Southall, Noel; Walsh, Martin J.; Brimacombe, Kyle R.; Leister, William; 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.; Jin, Shengfang; Dang, Lenny; Auld, Douglas S.; Park, Hee Won; Cantley, Lewis C.; Thomas, Craig J.; Vander Heiden, Matthew G.

In: Nature Chemical Biology, Vol. 8, No. 10, 2012, p. 839-847.

Research output: Contribution to journalArticle

Anastasiou, D, Yu, Y, Israelsen, WJ, Jiang, JK, Boxer, MB, Hong, BS, Tempel, W, Dimov, S, Shen, M, Jha, A, Yang, H, Mattaini, KR, Metallo, CM, Fiske, BP, Courtney, KD, Malstrom, S, Khan, TM, Kung, C, Skoumbourdis, AP, Veith, H, Southall, N, Walsh, MJ, Brimacombe, KR, Leister, W, Lunt, SY, Johnson, ZR, Yen, KE, Kunii, K, Davidson, SM, Christofk, HR, Austin, CP, Inglese, J, Harris, MH, Asara, JM, Stephanopoulos, G, Salituro, FG, Jin, S, Dang, L, Auld, DS, Park, HW, Cantley, LC, Thomas, CJ & Vander Heiden, MG 2012, 'Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis' Nature Chemical Biology, vol 8, no. 10, pp. 839-847. DOI: 10.1038/nchembio.1060
Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nature Chemical Biology. 2012;8(10):839-847. Available from, DOI: 10.1038/nchembio.1060

Anastasiou, Dimitrios; Yu, Yimin; Israelsen, William J.; Jiang, Jian Kang; Boxer, Matthew B.; Hong, Bum Soo; Tempel, Wolfram; Dimov, Svetoslav; Shen, Min; Jha, Abhishek; Yang, Hua; Mattaini, Katherine R.; Metallo, Christian M.; Fiske, Brian P.; Courtney, Kevin D.; Malstrom, Scott; Khan, Tahsin M.; Kung, Charles; Skoumbourdis, Amanda P.; Veith, Henrike; Southall, Noel; Walsh, Martin J.; Brimacombe, Kyle R.; Leister, William; 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.; Jin, Shengfang; Dang, Lenny; Auld, Douglas S.; Park, Hee Won; Cantley, Lewis C.; Thomas, Craig J.; Vander Heiden, Matthew G. / Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.

In: Nature Chemical Biology, Vol. 8, No. 10, 2012, p. 839-847.

Research output: Contribution to journalArticle

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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.",
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