IGF1 regulates PKM2 function through Akt phosphorylation

Cell Cycle. 2015;14(10):1559-67. doi: 10.1080/15384101.2015.1026490.

Abstract

Pyruvate kinase M2 (PKM2) acts at the crossroad of growth and metabolism pathways in cells. PKM2 regulation by growth factors can redirect glycolytic intermediates into key biosynthetic pathway. Here we show that IGF1 can regulate glycolysis rate, stimulate PKM2 Ser/Thr phosphorylation and decrease cellular pyruvate kinase activity. Upon IGF1 treatment we found an increase of the dimeric form of PKM2 and the enrichment of PKM2 in the nucleus. This effect was associated to a reduction of pyruvate kinase enzymatic activity and was reversed using metformin, which decreases Akt phosphorylation. IGF1 induced an increased nuclear localization of PKM2 and STAT3, which correlated with an increased HIF1α, HK2, and GLUT1 expression and glucose entrapment. Metformin inhibited HK2, GLUT1, HIF-1α expression and glucose consumption. These findings suggest a role of IGFIR/Akt axis in regulating glycolysis by Ser/Thr PKM2 phosphorylation in cancer cells.

Keywords: HIF1α; IGF1; IGFIR; PKM2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Proliferation / drug effects*
  • Dimerization
  • Glucose / metabolism
  • Glucose Transporter Type 1 / metabolism
  • Glycolysis / drug effects
  • Hexokinase / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Insulin-Like Growth Factor I / pharmacology*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Metformin / pharmacology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyruvate Kinase / metabolism
  • STAT3 Transcription Factor / metabolism
  • Thyroid Hormones / chemistry
  • Thyroid Hormones / metabolism*

Substances

  • Carrier Proteins
  • Glucose Transporter Type 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Proteins
  • STAT3 Transcription Factor
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • Insulin-Like Growth Factor I
  • Metformin
  • Hexokinase
  • Pyruvate Kinase
  • Proto-Oncogene Proteins c-akt
  • Glucose