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IGF1 regulates PKM2 function through Akt phosphorylation.

Barbara Salani1, Silvia Ravera, Adriana Amaro

  • 1a Department of Internal Medicine (DIMI) ; University of Genova ; Genova , Italy.

Cell Cycle (Georgetown, Tex.)
|March 20, 2015
PubMed
Summary
This summary is machine-generated.

Insulin-like growth factor 1 (IGF1) regulates cell metabolism by altering pyruvate kinase M2 (PKM2) activity and localization. Metformin reverses these effects, suggesting the IGF1R/Akt pathway influences cancer cell glycolysis.

Keywords:
HIF1αIGF1IGFIRPKM2

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Area of Science:

  • Cellular metabolism
  • Cancer biology
  • Molecular signaling

Background:

  • Pyruvate kinase M2 (PKM2) is a key enzyme regulating glycolysis and cellular biosynthesis.
  • Growth factors can influence metabolic pathways by modulating PKM2 activity.
  • Understanding PKM2 regulation is crucial for cancer therapy.

Purpose of the Study:

  • To investigate the role of Insulin-like Growth Factor 1 (IGF1) in regulating pyruvate kinase M2 (PKM2) activity and cellular metabolism.
  • To explore the effects of IGF1 on PKM2 phosphorylation, localization, and enzymatic activity.
  • To determine the potential of metformin in reversing IGF1-induced metabolic changes in cancer cells.

Main Methods:

  • Cellular treatment with IGF1 and metformin.
  • Analysis of PKM2 phosphorylation, dimerization, and subcellular localization (nuclear enrichment).
  • Measurement of pyruvate kinase enzymatic activity.
  • Assessment of downstream targets including STAT3, HIF1α, HK2, and GLUT1 expression.
  • Quantification of glucose uptake and consumption.

Main Results:

  • IGF1 treatment increased PKM2 Ser/Thr phosphorylation, leading to decreased pyruvate kinase activity and increased dimeric PKM2.
  • IGF1 promoted nuclear localization of PKM2 and STAT3, correlating with increased HIF1α, HK2, and GLUT1 expression and enhanced glucose uptake.
  • Metformin reversed IGF1-induced effects, including decreased Akt phosphorylation, reduced PKM2 activity, and inhibited expression of key glycolytic genes and glucose consumption.

Conclusions:

  • The IGF1R/Akt signaling axis plays a significant role in regulating glycolysis through Ser/Thr phosphorylation of PKM2 in cancer cells.
  • IGF1-induced metabolic reprogramming involves nuclear PKM2 and STAT3, promoting a pro-growth and glycolytic phenotype.
  • Metformin effectively counteracts IGF1-mediated metabolic alterations, highlighting its therapeutic potential in targeting cancer cell metabolism.