title: 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.affiliation: Department of Plastic Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; and.
authors.forename: Ayan
authors.initials: A
authors.lastname: Biswas
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; and.
authors.forename: Savita
authors.initials: S
authors.lastname: Khanna
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; and.
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
authors.affiliation: Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Xueliang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; and.
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
authors.affiliation: Department of Plastic Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; and gayle.gordillo@osumc.edu.
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Gordillo
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051379:Mice; D057507:Mice, 129 Strain; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011422:Propionates / Q000008:administration & dosage
chemical_list: D016227:Benzoquinones; D011422:Propionates; C075569:E 3330; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
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