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Small molecule activation of PKM2 in cancer cells induces serine auxotrophy

Charles Kung1, Jeff Hixon, Sung Choe

  • 1Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.

Chemistry & Biology
|September 25, 2012
PubMed

Insights

New activators of pyruvate kinase M2 (PKM2) reveal a link between glucose and amino acid metabolism in cancer. PKM2 activation creates a dependency on serine for tumor cell proliferation.

Area of Science:

  • Molecular Biology
  • Cancer Metabolism
  • Biochemistry

Background:

  • Tumor cells rely on aerobic glycolysis to meet high metabolic demands.
  • The lower-activity PKM2 isoform is paradoxically upregulated, seemingly constraining glycolysis.
  • Understanding PKM2 regulation is crucial for targeting cancer metabolism.

Purpose of the Study:

  • To discover novel PKM2 activators.
  • To investigate the metabolic consequences of PKM2 activation in cancer cells.
  • To explore the relationship between glucose and amino acid metabolism under PKM2 activation.

Main Methods:

  • Discovery and characterization of PKM2 activators with a unique allosteric binding mode.
  • Analysis of metabolic rewiring in cancer cells upon PKM2 activation.
  • Assessment of serine dependency and transporter expression.

Main Results:

  • PKM2 activators were identified, exhibiting a novel allosteric binding mechanism.
  • PKM2 activation induced a metabolic shift, creating a dependency on serine for proliferation (serine auxotrophy).
  • This metabolic rewiring involved reduced serine biosynthesis and increased serine transporter expression.

Conclusions:

  • PKM2 activation links glucose metabolism to amino acid dependency, specifically serine.
  • PKM2 activation reprograms cancer cell metabolism, making them reliant on serine.
  • PKM2 activity may confer metabolic flexibility, enabling cancer cells to adapt to nutrient stress.

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