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Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells
Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine...
Autores principales: | , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2005
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361553/ https://www.ncbi.nlm.nih.gov/pubmed/15956974 http://dx.doi.org/10.1038/sj.bjc.6602663 |
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author | Wey, J S Gray, M J Fan, F Belcheva, A McCarty, M F Stoeltzing, O Somcio, R Liu, W Evans, D B Klagsbrun, M Gallick, G E Ellis, L M |
author_facet | Wey, J S Gray, M J Fan, F Belcheva, A McCarty, M F Stoeltzing, O Somcio, R Liu, W Evans, D B Klagsbrun, M Gallick, G E Ellis, L M |
author_sort | Wey, J S |
collection | PubMed |
description | Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by >30% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing >50% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy. |
format | Text |
id | pubmed-2361553 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2005 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-23615532009-09-10 Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells Wey, J S Gray, M J Fan, F Belcheva, A McCarty, M F Stoeltzing, O Somcio, R Liu, W Evans, D B Klagsbrun, M Gallick, G E Ellis, L M Br J Cancer Molecular Diagnostics Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by >30% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing >50% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy. Nature Publishing Group 2005-07-25 2005-06-14 /pmc/articles/PMC2361553/ /pubmed/15956974 http://dx.doi.org/10.1038/sj.bjc.6602663 Text en Copyright © 2005 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Molecular Diagnostics Wey, J S Gray, M J Fan, F Belcheva, A McCarty, M F Stoeltzing, O Somcio, R Liu, W Evans, D B Klagsbrun, M Gallick, G E Ellis, L M Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells |
title | Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells |
title_full | Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells |
title_fullStr | Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells |
title_full_unstemmed | Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells |
title_short | Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells |
title_sort | overexpression of neuropilin-1 promotes constitutive mapk signalling and chemoresistance in pancreatic cancer cells |
topic | Molecular Diagnostics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361553/ https://www.ncbi.nlm.nih.gov/pubmed/15956974 http://dx.doi.org/10.1038/sj.bjc.6602663 |
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