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PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling
The aim of this study was to investigate the underlying mechanisms that transforming growth factor-β (TGF-β)-mediated epithelial-to-mesenchymal transition (EMT) in tumor cells contributes to 5-FU resistance. A series of experiments involving cell viability and caspase activity analyses, siRNA transf...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cognizant Communication Corporation
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848255/ https://www.ncbi.nlm.nih.gov/pubmed/30841957 http://dx.doi.org/10.3727/096504018X15442985680348 |
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author | Quan, Qiuying Zhong, Fengyun Wang, Xinwei Chen, Kai Guo, Lingchuan |
author_facet | Quan, Qiuying Zhong, Fengyun Wang, Xinwei Chen, Kai Guo, Lingchuan |
author_sort | Quan, Qiuying |
collection | PubMed |
description | The aim of this study was to investigate the underlying mechanisms that transforming growth factor-β (TGF-β)-mediated epithelial-to-mesenchymal transition (EMT) in tumor cells contributes to 5-FU resistance. A series of experiments involving cell viability and caspase activity analyses, siRNA transfection, RNA isolation, and quantitative-PCR (qPCR) assay, cell migration analysis, Western blotting analysis of total protein and membrane protein were performed in this study. Mouse xenograft model was used to determine the effect of the PAR2 inhibitor in vivo. In this study, we found that protease-activated receptor 2 (PAR2) induction in 5-FU therapy is correlated with TGF-β-mediated EMT and apoptosis resistance. PAR2 and TGF-β were both activated in response to 5-FU treatment in vivo and in vitro, and whereas TGF-β inhibition sensitized CRC cells to 5-FU and suppressed cell migration, PAR2 activation eliminated the effect of TGF-β inhibition. Conversely, siRNA-mediated PAR2 depletion or PAR2 inhibition with a specific inhibitor produced a similar phenotype as TGF-β signal inhibition: 5-FU sensitization and cell migration suppression. Moreover, the results of xenograft experiments indicated that the PAR2 inhibitor can enhance cell killing by 5-FU in vivo and suppress EMT signaling. Our results reveal that the TGF-β effects require the coordinating action of PAR2, suggesting that PAR2 inhibition could be a new therapeutic strategy to combat 5-FU resistance in CRC. |
format | Online Article Text |
id | pubmed-7848255 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cognizant Communication Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-78482552021-02-16 PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling Quan, Qiuying Zhong, Fengyun Wang, Xinwei Chen, Kai Guo, Lingchuan Oncol Res Article The aim of this study was to investigate the underlying mechanisms that transforming growth factor-β (TGF-β)-mediated epithelial-to-mesenchymal transition (EMT) in tumor cells contributes to 5-FU resistance. A series of experiments involving cell viability and caspase activity analyses, siRNA transfection, RNA isolation, and quantitative-PCR (qPCR) assay, cell migration analysis, Western blotting analysis of total protein and membrane protein were performed in this study. Mouse xenograft model was used to determine the effect of the PAR2 inhibitor in vivo. In this study, we found that protease-activated receptor 2 (PAR2) induction in 5-FU therapy is correlated with TGF-β-mediated EMT and apoptosis resistance. PAR2 and TGF-β were both activated in response to 5-FU treatment in vivo and in vitro, and whereas TGF-β inhibition sensitized CRC cells to 5-FU and suppressed cell migration, PAR2 activation eliminated the effect of TGF-β inhibition. Conversely, siRNA-mediated PAR2 depletion or PAR2 inhibition with a specific inhibitor produced a similar phenotype as TGF-β signal inhibition: 5-FU sensitization and cell migration suppression. Moreover, the results of xenograft experiments indicated that the PAR2 inhibitor can enhance cell killing by 5-FU in vivo and suppress EMT signaling. Our results reveal that the TGF-β effects require the coordinating action of PAR2, suggesting that PAR2 inhibition could be a new therapeutic strategy to combat 5-FU resistance in CRC. Cognizant Communication Corporation 2019-07-12 /pmc/articles/PMC7848255/ /pubmed/30841957 http://dx.doi.org/10.3727/096504018X15442985680348 Text en Copyright © 2019 Cognizant, LLC. http://creativecommons.org/licenses/by-nc-nd/4.0/ This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License. |
spellingShingle | Article Quan, Qiuying Zhong, Fengyun Wang, Xinwei Chen, Kai Guo, Lingchuan PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling |
title | PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling |
title_full | PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling |
title_fullStr | PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling |
title_full_unstemmed | PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling |
title_short | PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling |
title_sort | par2 inhibition enhanced the sensitivity of colorectal cancer cells to 5-fu and reduced emt signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848255/ https://www.ncbi.nlm.nih.gov/pubmed/30841957 http://dx.doi.org/10.3727/096504018X15442985680348 |
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