Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity

Abstract

BACKGROUND: Neuropilin-1 (NRP1) is a non-tyrosine kinase receptor for vascular endothelial growth factor (VEGF) recently implicated in tumour functions. METHODS: In this study we used a specific antagonist of VEGF binding to the NRP1 b1 domain, EG3287, to investigate the functional roles of NRP1 in human carcinoma cell lines, non-small-cell lung A549, kidney ACHN, and prostate DU145 cells expressing NRP1, and the underlying mechanisms involved. RESULTS: EG3287 potently displaced the specific binding of VEGF to NRP1 in carcinoma cell lines and significantly inhibited the migration of A549 and ACHN cells. Neuropilin-1 downregulation by siRNA also decreased cell migration. EG3287 reduced the adhesion of A549 and ACHN cells to extracellular matrix (ECM), and enhanced the anti-adhesive effects of a b1-integrin functionblocking antibody. EG3287 increased the cytotoxic effects of the chemotherapeutic agents 5-FU, paclitaxel, or cisplatin on A549 and DU145 cells, through inhibition of integrin-dependent cell interaction with the ECM. CONCLUSIONS: These findings indicate that NRP1 is important for tumour cell migration and adhesion, and that NRP1 antagonism enhances chemosensitivity, at least in part, by interfering with integrin-dependent survival pathways. A major implication of this study is that therapeutic strategies targeting NRP1 in tumour cells may be particularly useful in combination with other drugs for combating tumour survival, growth, and metastatic spread independently of an antiangiogenic effect of blocking NRP1.

Quantitative ratiometric discrimination between noncancerous and cancerous prostate cells based on neuropilin-1 overexpression

“…S1), and also enters many types through endocytosis (19). The second SBTuses the peptide Cys-RPARPAR, which specifically binds to a pocket in the biomarker protein NRP-1, (20) a receptor expressed on the outer plasma membrane of certain types of cancer cells, which is involved in angiogenesis, a hallmark of cancer growth, and tumor cell migration (21). The binding ability of the RPARPAR peptide to the NRP-1 receptor is given by the amino acid sequence that follows the so-called C-end rule (CendR): a C-terminal arginine (or lysine) in a general sequence of the type R/KXXR/K (where X indicates a generic amino acid) is fundamental for the binding activity of the peptide (20).…”

Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis

“…NRP1 is a well-described angiogenesis-associated gene, with additional roles in axon guidance, cell survival, migration, and invasion (17)(18)(19)(20)(21)(22). NRP-1 serves as a receptor to both VEGF and semaphorin (SEMA3A) family members.…”

Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP-ribose)-polymerase leading to reduced cerebrovascular apoptosis

“…NP-1 is also a semaphorin receptor in neuronal cell guidance (Fujisawa and Kitsukawa 1998) and is expressed, next to vessels, on neurons, T-cells, dendritic cells (Lepelletier et al 2007;Gu et al 2003) and migrating cancer cells (Jia et al 2010). NP-1 transgene and gene deletion mouse models indicate its essential role in angiogenesis, capillary formation, cardiovascular development (Kitsukawa et al 1997;Kawasaki et al 1999) and brain vessel formation (Kitsukawa et al 1995).…”