Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity.
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 beta1-integrin function-blocking 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.
Jia
H
H
Centre for Cardiovascular Biology and Medicine, Department of Medicine, The Rayne Building, University College London, 5 University Street, London WC1E 6JJ, UK. haiyan.jia@ucl.ac.uk
Cheng
L
L
Tickner
M
M
Bagherzadeh
A
A
Selwood
D
D
Zachary
I
I
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005353:Fibronectins / Q000494:pharmacology; D006801:Humans; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005353:Fibronectins; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C511613:vascular endothelial growth factor A (138-165); D039942:Neuropilin-1; D017239:Paclitaxel