Endothelial cell tumor growth is Ape/ref-1 dependent

Am J Physiol Cell Physiol. 2015 Sep 1;309(5):C296-307. doi: 10.1152/ajpcell.00022.2015. Epub 2015 Jun 24.


Tumor-forming endothelial cells have highly elevated levels of Nox-4 that release H2O2 into the nucleus, which is generally not compatible with cell survival. We sought to identify compensatory mechanisms that enable tumor-forming endothelial cells to survive and proliferate under these conditions. Ape-1/ref-1 (Apex-1) is a multifunctional protein that promotes DNA binding of redox-sensitive transcription factors, such as AP-1, and repairs oxidative DNA damage. A validated mouse endothelial cell (EOMA) tumor model was used to demonstrate that Nox-4-derived H2O2 causes DNA oxidation that induces Apex-1 expression. Apex-1 functions as a chaperone to keep transcription factors in a reduced state. In EOMA cells Apex-1 enables AP-1 binding to the monocyte chemoattractant protein-1 (mcp-1) promoter and expression of that protein is required for endothelial cell tumor formation. Intraperitoneal injection of the small molecule inhibitor E3330, which specifically targets Apex-1 redox-sensitive functions, resulted in a 50% decrease in tumor volume compared with mice injected with vehicle control (n = 6 per group), indicating that endothelial cell tumor proliferation is dependent on Apex-1 expression. These are the first reported results to establish Nox-4 induction of Apex-1 as a mechanism promoting endothelial cell tumor formation.

Keywords: AP-1 transcription factor; DNA damage response; Nox-4; c-Jun transcription factor; endothelial cell; hemangioendothelioma; hemangioma; monocyte chemoattractant protein-1, Ape-1/ref-1; tumor cell biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzoquinones / administration & dosage
  • Cell Proliferation* / drug effects
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / antagonists & inhibitors
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / biosynthesis*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Female
  • Mice
  • Mice, 129 Strain
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Propionates / administration & dosage


  • Benzoquinones
  • Propionates
  • E 3330
  • Apex1 protein, mouse
  • DNA-(Apurinic or Apyrimidinic Site) Lyase