| First Author | Biswas A | Year | 2015 |
| Journal | Am J Physiol Cell Physiol | Volume | 309 |
| Issue | 5 | Pages | C296-307 |
| PubMed ID | 26108661 | Mgi Jnum | J:228670 |
| Mgi Id | MGI:5708446 | Doi | 10.1152/ajpcell.00022.2015 |
| Citation | Biswas A, et al. (2015) Endothelial cell tumor growth is Ape/ref-1 dependent. Am J Physiol Cell Physiol 309(5):C296-307 |
| abstractText | 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. |
