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Glutamine Flux Imaging Using Genetically Encoded Sensors
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PKM2 promotes reductive glutamine metabolism.

Miao Liu1, Yuanyuan Wang1, Yuxia Ruan1

  • 1Department of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.

Cancer Biology & Medicine
|March 21, 2019
PubMed
Summary

Pyruvate kinase M2 (PKM2) drives aerobic glycolysis and reductive glutamine metabolism, enhancing cancer cell proliferation under hypoxia. PKM2 also influences tumor-associated stromal cells, impacting overall tumor growth.

Keywords:
PKM2The Warburg effectglucose metabolismproton homeostasisthe reverse Warburg effect

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Metabolism

Background:

  • Pyruvate kinases M (PKM), encompassing PKM1 and PKM2 isoforms, are key regulators of glucose metabolism.
  • PKM2 is known to promote aerobic glycolysis, a metabolic shift characteristic of cancer cells, often referred to as the Warburg effect.

Purpose of the Study:

  • To elucidate the specific roles of PKM2 in regulating cellular metabolism.
  • To understand how PKM2 influences metabolic pathways beyond glycolysis.

Main Methods:

  • CRISPR/Cas9 gene editing was employed to create PKM-knockout cell models.
  • Quantitative analysis of lactate and glucose levels using autoanalyzers.
  • Metabolic flux analysis of 13C-labeled glucose and glutamine via liquid chromatography/mass spectrometry.
  • In vivo assessment of PKM's impact on tumor growth in mouse models.

Main Results:

  • Both PKM1 and PKM2 support aerobic glycolysis, with PKM2 exhibiting higher efficiency in converting glucose to lactate.
  • PKM2 was found to decrease intracellular glucose availability for pathways like citrate production, thereby increasing the alpha-ketoglutarate/citrate ratio.
  • This metabolic shift promotes glutamine-derived acetyl-CoA generation via the reductive pathway, supporting cell proliferation under hypoxia and tumor growth.
  • PKM deletion induced a reverse Warburg effect in tumor-associated stromal cells.

Conclusions:

  • PKM2 is crucial for promoting reductive glutamine metabolism and maintaining cellular proton homeostasis.
  • The findings enhance the understanding of PKM2's physiological functions within cancer cells and its contribution to the tumor microenvironment.