Glucose-Induced Oxidative Stress Reduces Proliferation in Embryonic Stem Cells via FOXO3A/β-Catenin-Dependent Transcription of p21(cip1)

Stem Cell Reports. 2016 Jul 12;7(1):55-68. doi: 10.1016/j.stemcr.2016.06.006.


Embryonic stem cells (ESCs), which are derived from a peri-implantation embryo, are routinely cultured in medium containing diabetic glucose (Glc) concentrations. While pregnancy in women with pre-existing diabetes may result in small embryos, whether such high Glc levels affect ESC growth remains uncovered. We show here that long-term exposure of ESCs to diabetic Glc inhibits their proliferation, thereby mimicking in vivo findings. Molecularly, Glc exposure increased oxidative stress and activated Forkhead box O3a (FOXO3a), promoting increased expression and activity of the ROS-removal enzymes superoxide dismutase and catalase and the cell-cycle inhibitors p21(cip1) and p27(kip1). Diabetic Glc also promoted β-catenin nuclear localization and the formation of a complex with FOXO3a that localized to the promoters of Sod2, p21(cip1), and potentially p27(kip1). Our results demonstrate an adaptive response to increases in oxidative stress induced by diabetic Glc conditions that promote ROS removal, but also result in a decrease in proliferation.

Keywords: AKT; FOXO; c-jun kinase; embryonic stem cell; glucose; metabolism; oxidative stress; proliferation; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Culture Media / toxicity
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Embryonic Stem Cells / drug effects*
  • Embryonic Stem Cells / pathology
  • Forkhead Box Protein O3 / genetics*
  • Gene Expression Regulation / drug effects
  • Glucose / toxicity*
  • Humans
  • Oxidative Stress / drug effects*
  • Phosphatidylinositol 3-Kinases / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • Signal Transduction
  • Superoxide Dismutase / genetics
  • Transcription, Genetic / drug effects
  • beta Catenin / genetics*


  • CDKN1B protein, human
  • Culture Media
  • Cyclin-Dependent Kinase Inhibitor p21
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • beta Catenin
  • Cyclin-Dependent Kinase Inhibitor p27
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose