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.
| Original language | English |
|---|---|
| Pages (from-to) | 2945-2957 |
| Number of pages | 13 |
| Journal | Nucleic Acids Research |
| Volume | 42 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2014 |
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ASJC Scopus subject areas
- Genetics
Cite this
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.
In: Nucleic Acids Research, Vol. 42, No. 5, 2014, p. 2945-2957.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Evidence for G-quadruplex in the promoter of vegfr-2 and its targeting to inhibit tumor angiogenesis
AU - Salvati, Erica
AU - Zizza, Pasquale
AU - Rizzo, Angela
AU - Iachettini, Sara
AU - Cingolani, Chiara
AU - D'angelo, Carmen
AU - Porru, Manuela
AU - Randazzo, Antonio
AU - Pagano, Bruno
AU - Novellino, Ettore
AU - Pisanu, Maria Elena
AU - Stoppacciaro, Antonella
AU - Spinella, Francesca
AU - Bagnato, Anna
AU - Gilson, Eric
AU - Leonetti, Carlo
AU - Biroccio, Annamaria
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84898954191&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84898954191&partnerID=8YFLogxK
U2 - 10.1093/nar/gkt1289
DO - 10.1093/nar/gkt1289
M3 - Article
C2 - 24335081
AN - SCOPUS:84898954191
VL - 42
SP - 2945
EP - 2957
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 5
ER -