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The CXCL12/CXCR4/ACKR3 Signaling Axis Regulates PKM2 and Glycolysis

Kathryn E Luker1, Gary D Luker1,2,3

  • 1Department of Radiology, Center for Molecular Imaging, University of Michigan Medical School, 109 Zina Pitcher Place, A524 BSRB, Ann Arbor, MI 48109-2200, USA.

Cells
|June 10, 2022
PubMed

Insights

CXCL12 signaling via CXCR4 and ACKR3 alters protein interactions, reducing pyruvate kinase M2 (PKM2) activity and reprogramming glucose metabolism in cancer. This impacts cell glycolysis and prognosis.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Metabolic Pathways

Background:

  • CXCL12 (chemokine ligand) and its receptors CXCR4 and ACKR3 are crucial in cancer progression.
  • β-arrestin 2 links these receptors to signaling pathways and interacts with pyruvate kinase M2 (PKM2), an enzyme involved in cancer metabolism.
  • Dysregulated PKM2 activity and altered cellular metabolism are hallmarks of cancer, contributing to poor prognosis.

Purpose of the Study:

  • To investigate how CXCL12 signaling through CXCR4 and ACKR3 influences protein interactions within the β-arrestin-ERK-PKM2 pathway.
  • To determine the effect of CXCL12 signaling on PKM2 oligomerization and enzymatic activity.
  • To analyze the impact of CXCL12 signaling on glucose metabolism, including glycolysis and the pentose phosphate pathway.

Main Methods:

  • Cell-based assays using luciferase complementation to study protein interactions.
  • Tumor xenograft model of breast cancer in NSG mice.
  • Mass spectrometry to analyze protein interactions and glucose metabolism with isotopically labeled glucose.

Main Results:

  • CXCL12 signaling stimulated protein interactions among β-arrestin 2, PKM2, ERK2, and receptors CXCR4/ACKR3.
  • PKM2 dissociated from β-arrestin 2, and its oligomerization decreased, shifting towards less active dimers/monomers.
  • CXCL12 signaling increased intermediate metabolites in glycolysis and the pentose phosphate pathway, with ACKR3 showing a more significant effect.

Conclusions:

  • CXCL12 signaling reprograms cellular metabolism by regulating PKM2 interactions and oligomerization.
  • The CXCR4/ACKR3-β-arrestin 2-PKM2 axis is a key regulator of metabolic shifts in cancer.
  • Targeting this pathway could offer novel therapeutic strategies for cancer treatment.
Keywords:
bioluminescence imagingcancer metabolismchemokinesluciferase complementation

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