Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis

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...

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Main Authors:	Salvati, Erica, Zizza, Pasquale, Rizzo, Angela, Iachettini, Sara, Cingolani, Chiara, D’Angelo, Carmen, Porru, Manuela, Randazzo, Antonio, Pagano, Bruno, Novellino, Ettore, Pisanu, Maria Elena, Stoppacciaro, Antonella, Spinella, Francesca, Bagnato, Anna, Gilson, Eric, Leonetti, Carlo, Biroccio, Annamaria
Format:	Online
Language:	English
Published:	Oxford University Press 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950687/

id	pubmed-3950687
recordtype	oai_dc
spelling	pubmed-39506872014-03-12 Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis Salvati, Erica Zizza, Pasquale Rizzo, Angela Iachettini, Sara Cingolani, Chiara D’Angelo, Carmen Porru, Manuela Randazzo, Antonio Pagano, Bruno Novellino, Ettore Pisanu, Maria Elena Stoppacciaro, Antonella Spinella, Francesca Bagnato, Anna Gilson, Eric Leonetti, Carlo Biroccio, Annamaria 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. Oxford University Press 2014-03 2013-12-11 /pmc/articles/PMC3950687/ /pubmed/24335081 http://dx.doi.org/10.1093/nar/gkt1289 Text en © The Author(s) 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Salvati, Erica Zizza, Pasquale Rizzo, Angela Iachettini, Sara Cingolani, Chiara D’Angelo, Carmen Porru, Manuela Randazzo, Antonio Pagano, Bruno Novellino, Ettore Pisanu, Maria Elena Stoppacciaro, Antonella Spinella, Francesca Bagnato, Anna Gilson, Eric Leonetti, Carlo Biroccio, Annamaria
spellingShingle	Salvati, Erica Zizza, Pasquale Rizzo, Angela Iachettini, Sara Cingolani, Chiara D’Angelo, Carmen Porru, Manuela Randazzo, Antonio Pagano, Bruno Novellino, Ettore Pisanu, Maria Elena Stoppacciaro, Antonella Spinella, Francesca Bagnato, Anna Gilson, Eric Leonetti, Carlo Biroccio, Annamaria Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis
author_facet	Salvati, Erica Zizza, Pasquale Rizzo, Angela Iachettini, Sara Cingolani, Chiara D’Angelo, Carmen Porru, Manuela Randazzo, Antonio Pagano, Bruno Novellino, Ettore Pisanu, Maria Elena Stoppacciaro, Antonella Spinella, Francesca Bagnato, Anna Gilson, Eric Leonetti, Carlo Biroccio, Annamaria
author_sort	Salvati, Erica
title	Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis
title_short	Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis
title_full	Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis
title_fullStr	Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis
title_full_unstemmed	Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis
title_sort	evidence for g-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis
description	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.
publisher	Oxford University Press
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950687/
_version_	1612066704756572160

Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis

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