Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo

Abstract

Angiogenesis in glioblastoma is largely dependent on vascular endothelial growth factor (VEGF) signalling. Consistently, the VEGF coreceptor NRP1 promotes angiogenesis and tumour growth in gliomas. Here, we provide data showing that an innovative peptidic tool targeting the transmembrane domain of NRP1 efficiently blocks rat and human glioma growth in vivo. We show both in vivo and in vitro that the antitumour effect results from the anti-proliferative, anti-migratory and antiangiogenic properties of the compound. The proposed NRP1 antagonizing peptide is therefore a promising novel class of anti-angiogenic drugs that might prolong glioma patient survival. Our results finally show for the first time that the transmembrane domain of important signalling receptors can be antagonized in vivo thereby providing a new avenue towards the development of atypical antagonists with strong therapeutic potential.

Neuropilin-1–Dependent Regulation of EGF-Receptor Signaling

“…This is consistent with previous evidence that deleting the "c"/MAM oligomerization domain impairs neuropilin function (5). Moreover, a synthetic peptide derived from the transmembrane segment of Nrp1 prevents Nrp1 dimerization and oligomerization and blocks glioma growth in mice (28).…”

Single-spanning transmembrane domains in cell growth and cell-cell interactions

“…Moreover, our data demonstrate in orthotopic and heterotopic graft models of brain tumors that the growth of rat and human glioma is strongly reduced (up to 80%) in the presence of the peptide. 103 Thus, this preclinical study suggests that targeting TM domain interactions possibly represents a clear alternative to current protein inhibitors.…”

“…[100][101][102][103] One very recent example is the demonstration by some of us that a synthetic peptide mimicking the transmembrane domain of Neuropilin-1 (NRP1) blocks the biological functions of this Plexin and VEGFR coreceptor. 136 The sequence of this TM domain contains two…”

Concurrent Expression of VEGF-C and Neuropilin-2 Is Correlated with Poor Prognosis in Glioblastoma

“…NRP1 was considered as a co-receptor for VEGF-induced angiogenesis, and interference of NRP1 could inhibit growth of glioma in vivo (Broholm and Laursen 2004;Nasarre et al 2010). Moreover, autocrine VEGF-VEGFR2-NRP1 signaling was demonstrated to promote glioma stemlike cell viability and tumor growth.…”

“…NRPs were reported to interact with VEGF receptors (VEGFR1 and VEGFR2) and other receptors (Sulpice et al 2008). Importantly, NRP1 was demonstrated to promote the viability of stem-like cell and tumor growth of glioma, and NRP1 interference could inhibit glioma growth in vivo and in vitro (Nasarre et al 2010;Li et al 2011;Hamerlik et al 2012). Compared with the breakthrough of NRP1 research in glioma, the role of NRP2 has not been well elucidated, except for the study proving that NRP2 could promote the growth and clonogenicity of glioblastoma multiforme cell lines (Epis et al 2014).…”