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Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses

Dimitrios Anastasiou1, George Poulogiannis, John M Asara

  • 1Beth Israel Deaconess Medical Center, Department of Medicine-Division of Signal Transduction, Boston, MA 02115, USA.

Science (New York, N.Y.)
|November 5, 2011
PubMed

Insights

Cancer cells control reactive oxygen species (ROS) using pyruvate kinase M2 (PKM2). Oxidized PKM2 diverts glucose to the pentose phosphate pathway, aiding ROS detoxification and tumor formation.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Cell Metabolism

Background:

  • Intracellular reactive oxygen species (ROS) concentrations are critical for cancer cell survival.
  • Pyruvate kinase M2 (PKM2) plays a key role in cancer cell metabolism and proliferation.

Purpose of the Study:

  • To investigate the role of PKM2 in regulating intracellular ROS concentrations in human lung cancer cells.
  • To determine the mechanism by which ROS affects PKM2 activity.
  • To assess the impact of modulating PKM2 oxidation resistance on cancer cell survival and tumor formation.

Main Methods:

  • Utilized human lung cancer cell lines.
  • Investigated the effect of acute increases in intracellular ROS on PKM2 activity.
  • Analyzed the oxidation of Cys(358) in PKM2.
  • Employed site-directed mutagenesis to create an oxidation-resistant PKM2 mutant (Cys(358) to Ser(358)).
  • Assessed cancer cell sensitivity to oxidative stress.
  • Evaluated tumor formation in a xenograft mouse model.

Main Results:

  • Acute increases in intracellular ROS inhibited PKM2 through oxidation of Cys(358).
  • PKM2 inhibition by ROS is essential for diverting glucose flux into the pentose phosphate pathway.
  • This metabolic shift generates reducing potential for ROS detoxification.
  • Lung cancer cells with oxidation-resistant PKM2 showed increased sensitivity to oxidative stress.
  • Impaired tumor formation was observed in xenograft models using cells with oxidation-resistant PKM2.

Conclusions:

  • PKM2's regulatory properties allow cancer cells to withstand oxidative stress.
  • Modulating PKM2 oxidation offers a potential therapeutic strategy for targeting cancer cells.
  • PKM2's role extends beyond proliferation, contributing to cancer cell survival under oxidative stress.

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