title: Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis.
abstract: Tumor angiogenesis is mainly mediated by vascular endothelial growth factor (VEGF), a pro-angiogenic factor produced by cancer cells and active on the endothelium through the VEGF receptor 2 (VEGFR-2). Here we identify a G-rich sequence within the proximal promoter region of vegfr-2, able to form an antiparallel G-quadruplex (G4) structure. This G4 structure can be efficiently stabilized by small molecules with the consequent inhibition of vegfr-2 expression. Functionally, the G4-mediated reduction of VEGFR-2 protein causes a switching off of signaling components that, converging on actin cytoskeleton, regulate the cellular events leading to endothelial cell proliferation, migration and differentiation. As a result of endothelial cell function impairment, angiogenic process is strongly inhibited by G4 ligands both in vitro and in vivo. Interestingly, the G4-mediated antiangiogenic effect seems to recapitulate that observed by using a specific interference RNA against vegfr-2, and it is strongly antagonized by overexpressing the vegfr-2 gene. In conclusion, we describe the evidence for the existence of G4 in the promoter of vegfr-2, whose expression and function can be markedly inhibited by G4 ligands, thereby revealing a new, and so far undescribed, way to block VEGFR-2 as target for anticancer therapy.
authors: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy, Laboratory of Molecular Pathology, Department of Pharmacy, University of Naples "Federico II", Naples, Italy, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy, Laboratory of Molecular Pathology, Regina Elena National Cancer Institute, Rome, Italy, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice University, CNRS UMR7284/INSERM U1081, Faculty of Medicine, Nice, France and Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, France.
authors: Erica
authors: E
authors: Salvati
authors: Pasquale
authors: P
authors: Zizza
authors: Angela
authors: A
authors: Rizzo
authors: Sara
authors: S
authors: Iachettini
authors: Chiara
authors: C
authors: Cingolani
authors: Carmen
authors: C
authors: D'Angelo
authors: Manuela
authors: M
authors: Porru
authors: Antonio
authors: A
authors: Randazzo
authors: Bruno
authors: B
authors: Pagano
authors: Ettore
authors: E
authors: Novellino
authors: Maria Elena
authors: ME
authors: Pisanu
authors: Antonella
authors: A
authors: Stoppacciaro
authors: Francesca
authors: F
authors: Spinella
authors: Anna
authors: A
authors: Bagnato
authors: Eric
authors: E
authors: Gilson
authors: Carlo
authors: C
authors: Leonetti
authors: Annamaria
authors: A
authors: Biroccio
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054856:G-Quadruplexes; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D011401:Promoter Regions, Genetic; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D008024:Ligands; D040301:Vascular Endothelial Growth Factor Receptor-2