Endothelial cell tumor growth is Ape/ref-1 dependent.

Abstract

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.

• Authors: Ayan Biswas, Savita Khanna, Sashwati Roy, Xueliang Pan, Chandan K Sen, Gayle M Gordillo
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 309 Issue 5 Pg. C296-307 (Sep 01 2015) ISSN: 1522-1563 [Electronic] United States
• PMID: 26108661 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

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

Topics

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