Overexpression of VEGF189 in breast cancer cells induces apoptosis via NRP1 under stress conditions

Vintonenko, Nadejda; Pelaez-Garavito, Irma; Buteau-Lozano, Hélène; Toullec, Aurore; Lidereau, Rosette; Perret, Gérard-Yves; Bièche, Ivan; Perrot‐Applanat, Martine

doi:10.4161/cam.5.4.17287

Cited by 27 publications

(29 citation statements)

References 59 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ER (?) MCF-7 and ER (-) MDA-MB-231 breast cancer cells are all highly express NRP1 [30,31]. As observed in Fig.…”

Section: Ta1-irgd Increased the Inhibition Of Mcf-7 And Mda-mb-231 Cesupporting

confidence: 59%

A modified thymosin alpha 1 inhibits the growth of breast cancer both in vitro and in vivo: suppressment of cell proliferation, inducible cell apoptosis and enhancement of targeted anticancer effects

Lao

et al. 2015

Apoptosis

View full text Add to dashboard Cite

Thymosin alpha 1 (Tα1) is commonly used for treating several diseases; however its usage has been limited because of poor penetration of the target tissue, such as tumor cells. In the present study, Tα1-iRGD, a peptide by conjugating Tα1 with the iRGD fragment, was evaluated its performance in MCF-7 and MDA-MB-231 human breast cancer cells. Compared with the wild-type peptide, Tα1-iRGD was more selective in binding tumor cells in the cell attachment assay. Furthermore, the MTT assay confirmed that Tα1-iRGD proved more effective in significantly inhibiting the growth of MCF-7 cells in contrast to the general inhibition displayed by Tα1. Further, conjugation of Tα1 with iRGD preserved the immunomodulatory activity of the drug by increasing the proliferation of mouse spleen lymphocytes. Further, compared with Tα1 treatment, Tα1-iRGD treatment of MCF-7 cells considerably increased the number of cells undergoing apoptosis, resulting in a dose-dependent inhibition of cancer cell growth, which was associated with a much better effect on up-regulation of the expression of BCL2-associated X protein (Bax), caspase 9, etc. More importantly, treatment with Ta1-iRGD was more efficacious than treatment with Ta1 in vivo. This study highlights the importance of iRGD on enhancement of cell penetration and tumor accumulation. In summary, our findings demonstrate that the novel modified Tα1 developed in this study has the potential to be used for treating breast cancer.

show abstract

“…ER (?) MCF-7 and ER (-) MDA-MB-231 breast cancer cells are all highly express NRP1 [30,31]. As observed in Fig.…”

Section: Ta1-irgd Increased the Inhibition Of Mcf-7 And Mda-mb-231 Cesupporting

confidence: 59%

A modified thymosin alpha 1 inhibits the growth of breast cancer both in vitro and in vivo: suppressment of cell proliferation, inducible cell apoptosis and enhancement of targeted anticancer effects

Lao

et al. 2015

Apoptosis

View full text Add to dashboard Cite

show abstract

“…These effects have been often explained by the role of Nrp1 in supporting VEGF signaling (17,19,20). In contrast to these findings, in other studies, an elevated expression of Nrp1 was associated with more favorable prognosis of patients with colon cancer (21) and reduced tumor growth in experimental models in mice (22); moreover, a VEGF/Nrp1-dependent pathway suppressing cell viability has been proposed in 1 specific case (23). These discrepancies are currently unresolved and they might reflect cell-specific responses and/or the involvement of different signaling pathways.…”

Section: Introductioncontrasting

confidence: 44%

Neuropilin-1–Dependent Regulation of EGF-Receptor Signaling

et al. 2012

View full text Add to dashboard Cite

Neuropilin-1 (NRP1) is a coreceptor for multiple extracellular ligands. NRP1 is widely expressed in cancer cells and in advanced human tumors; however, its functional relevance and signaling mechanisms are unclear. Here, we show that NRP1 expression controls viability and proliferation of different cancer cells, independent of its short intracellular tail. We found that the extracellular domain of NRP1 interacts with the EGF receptor (EGFR) and promotes its signaling cascade elicited upon EGF or TGF-a stimulation. Upon NRP1 silencing, the ability of ligand-bound EGFR to cluster on the cell surface, internalize, and activate the downstream AKT pathway is severely impaired. EGFR is frequently activated in human tumors due to overexpression, mutation, or sustained autocrine/paracrine stimulation. Here we show that NRP1-blocking antibodies and NRP1 silencing can counteract ligand-induced EGFR activation in cancer cells. Thus our findings unveil a novel molecular mechanism by which NRP1 can control EGFR signaling and tumor growth. Cancer Res; 72(22); 5801-11. Ó2012 AACR.

show abstract

“…VEGF-A165a binds NRP1 with higher affinity than to NRP2 (k d ∼100–300 pM for NRP1 14 , 31 , ∼700 pM for NRP2 14 ; as noted in the previous section, the measured cell surface affinities are stronger than in cell-free systems). VEGFR2 phosphorylation on Y951 and Y1175 is lower for VEGF-A121a-ligated receptor complexes than for VEGF-A165a-ligated complexes in the presence of NRP1, but higher for VEGF-A121a-ligated complexes in the presence of NRP2 (Figure 5 of 15 ).…”

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 57%

“…11 , 14 , 31 VEGF-A121a, however, does not appear to bind to porcine aortic endothelial cells expressing only NRP1 11 . Shraga-Heled et al showed that VEGF-A121a binding affinity to VEGFR2 is ∼10 fold higher in the presence of NRPs 15 , and coexpression of NRPs and VEGFRs on the same endothelial cell may affect VEGF-A121a association with NRPs.…”

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 87%

“…Note that SPR measurements represent the affinities for the interaction of a ligand with monomeric truncated NRP1, comprising only the a1/12-b1/b2 domains and lacking the MAM domain known to induce NRP oligomerization, 28 the transmembrane domain known to homodimerize 29 and the NRP1 GAG modification 30 , which may explain why these SPR-measured affinities are lower than those measured for on-cell VEGF-NRP interactions. 31 …”

Section: Evidence Supporting Direct Vegf-a121a Binding To Neuropilinsmentioning

confidence: 99%

See 1 more Smart Citation

VEGF-A121a binding to Neuropilins – A concept revisited

Sarabipour

Gabhann

2017

Cell Adhesion & Migration

View full text Add to dashboard Cite

All known splice isoforms of vascular endothelial growth factor A (VEGF-A) can bind to the receptor tyrosine kinases VEGFR-1 and VEGFR-2. We focus here on VEGF-A121a and VEGF-A165a, two of the most abundant VEGF-A splice isoforms in human tissue1, and their ability to bind the Neuropilin co-receptors NRP1 and NRP2. The Neuropilins are key vascular, immune, and nervous system receptors on endothelial cells, neuronal axons, and regulatory T cells respectively. They serve as co-receptors for the Plexins in Semaphorin binding on neuronal and vascular endothelial cells, and for the VEGFRs in VEGF binding on vascular and lymphatic endothelial cells, and thus regulate the initiation and coordination of cell signaling by Semaphorins and VEGFs.2 There is conflicting evidence in the literature as to whether only heparin-binding VEGF-A isoforms – that is, isoforms with domains encoded by exons 6 and/or 7 plus 8a – bind to Neuropilins on endothelial cells. While it is clear that VEGF-A165a binds to both NRP1 and NRP2, published studies do not all agree on the ability of VEGF-A121a to bind NRPs. Here, we review and attempt to reconcile evidence for and against VEGF-A121a binding to Neuropilins. This evidence suggests that, in vitro, VEGF-A121a can bind to both NRP1 and NRP2 via domains encoded by exons 5 and 8a; in the case of NRP1, VEGF-A121a binds with lower affinity than VEGF-A165a. In in vitro cell culture experiments, both NRP1 and NRP2 can enhance VEGF-A121a-induced phosphorylation of VEGFR2 and downstream signaling including proliferation. However, unlike VEGFA-165a, experiments have shown that VEGF-A121a does not ‘bridge’ VEGFR2 and NRP1, i.e. it does not bind both receptors simultaneously at their extracellular domain. Thus, the mechanism by which Neuropilins potentiate VEGF-A121a-mediated VEGFR2 signaling may be different from that for VEGF-A165a. We suggest such an alternate mechanism: interactions between NRP1 and VEGFR2 transmembrane (TM) and intracellular (IC) domains.

show abstract

Overexpression of VEGF189 in breast cancer cells induces apoptosis via NRP1 under stress conditions

Cited by 27 publications

References 59 publications

A modified thymosin alpha 1 inhibits the growth of breast cancer both in vitro and in vivo: suppressment of cell proliferation, inducible cell apoptosis and enhancement of targeted anticancer effects

A modified thymosin alpha 1 inhibits the growth of breast cancer both in vitro and in vivo: suppressment of cell proliferation, inducible cell apoptosis and enhancement of targeted anticancer effects

Neuropilin-1–Dependent Regulation of EGF-Receptor Signaling

VEGF-A121a binding to Neuropilins – A concept revisited

Contact Info

Product

Resources

About