title: Mitochondrial UQCRB regulates VEGFR2 signaling in endothelial cells.
abstract: Vascular endothelial growth factor (VEGF) signal transduction is involved in tumor angiogenesis, and the inhibition of this pathway is considered to be a powerful strategy for cancer therapy. We previously showed that small molecules targeting the ubiquinol-cytochrome c reductase binding protein (UQCRB), a subunit of mitochondrial complex III, in tumor cells suppress hypoxia-induced tumor angiogenesis. However, the mechanism by which UQCRB functioned remained unknown. In the present study, we demonstrate in endothelial cells (ECs) that UQCRB enhances VEGF receptor type 2 (VEGFR2) signaling by increasing the levels of mitochondrial reactive oxygen species (ROS). By contrast, terpestacin, a UQCRB targeting small molecule, blocked mitochondrial ROS-mediated VEGFR2 signaling pathways in ECs, thereby suppressing VEGF-dependent angiogenesis in vitro and in vivo. Furthermore, treatment with both terpestacin and bevacizumab, a VEGF signaling inhibitor, resulted in additive inhibition of tumor-induced angiogenesis both in vitro and in vivo. These data demonstrate that mitochondrial UQCRB positively regulates VEGFR2 signaling in ECs and the UQCRB targeting agent could be applied in new therapeutic approaches for human cancer.
  
  
  CONCLUSIONS
  Inhibiting angiogenesis has been a focus for anti-cancer strategies. Mitochondrial UQCRB enhances VEGFR2 signaling by increasing ROS in endothelial cells. UQCRB inhibitor blocks angiogenesis by suppressing mitochondrial ROS. Findings may provide a new therapeutic approach for human cancer.
authors.affiliation: Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, South Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Yonghyo
authors.initials: Y
authors.lastname: Kim
authors.forename: Junghwa
authors.initials: J
authors.lastname: Chang
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
mesh_terms: D020533:Angiogenesis Inhibitors; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000068258:Bevacizumab; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000502:physiology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D001643:Bridged Bicyclo Compounds; D002352:Carrier Proteins; D017382:Reactive Oxygen Species; C027208:ubiquinone-binding proteins; C080890:terpestacin; D000068258:Bevacizumab; D040301:Vascular Endothelial Growth Factor Receptor-2