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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...

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Detalles Bibliográficos
Autores principales: Quan, Qiuying, Zhong, Fengyun, Wang, Xinwei, Chen, Kai, Guo, Lingchuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cognizant Communication Corporation 2019
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.
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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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