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Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Dimitrios Anastasiou1, Yimin Yu, William J Israelsen

  • 1Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Nature Chemical Biology
|August 28, 2012
PubMed

Insights

Activating pyruvate kinase M2 (PKM2) with small molecules or expressing PKM1 inhibits cancer growth. This approach disrupts cancer

Area of Science:

  • Cancer Metabolism
  • Enzyme Regulation
  • Molecular Oncology

Background:

  • Cancer cells exhibit altered glucose metabolism to support proliferation.
  • Pyruvate kinase M2 (PKM2) plays a key role in regulating cancer metabolism.
  • PKM2 activity is inhibited by tyrosine-phosphorylated proteins, favoring biosynthesis.

Purpose of the Study:

  • To investigate the therapeutic potential of modulating pyruvate kinase activity in cancer.
  • To explore the mechanism of small-molecule PKM2 activators.

Main Methods:

  • Expression of PKM1 and treatment with small-molecule PKM2 activators in xenograft tumor models.
  • Biochemical assays to study PKM2 activity and its interaction with activators and inhibitors.
  • Structural studies of PKM2 bound to small-molecule activators.

Main Results:

  • PKM1 expression or PKM2 activation by small molecules significantly inhibited xenograft tumor growth.
  • Small-molecule activators bind PKM2 at a distinct site from fructose-1,6-bisphosphate (FBP).
  • Activator binding confers a constitutively active PKM2 state resistant to tyrosine-phosphorylated protein inhibition.

Conclusions:

  • Targeting PKM2 with small-molecule activators represents a viable strategy to suppress tumor growth.
  • PKM2 activation interferes with cancer's anabolic metabolism by overcoming inhibitory signals.
  • This approach offers a novel therapeutic avenue in oncology.

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