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TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway

Radiotherapy is used to treat gastric cancer (GC); however, radioresistance challenges the clinical outcomes of GC, and the mechanisms of radioresistance in GC remain poorly understood. Here, we report that the TGF-β receptor inhibitor, LY2109761 (LY), is a potential radiosensitizer both in vitro an...

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Autores principales: Yang, Tian, Huang, Tianhe, Zhang, Dongdong, Wang, Miao, Wu, Balu, Shang, Yufeng, Sattar, Safat, Ding, Lu, Liu, Yin, Jiang, Hongqiang, Liang, Yuxing, Zhou, Fuling, Wei, Yongchang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834415/
https://www.ncbi.nlm.nih.gov/pubmed/31631064
http://dx.doi.org/10.18632/aging.102329
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author Yang, Tian
Huang, Tianhe
Zhang, Dongdong
Wang, Miao
Wu, Balu
Shang, Yufeng
Sattar, Safat
Ding, Lu
Liu, Yin
Jiang, Hongqiang
Liang, Yuxing
Zhou, Fuling
Wei, Yongchang
author_facet Yang, Tian
Huang, Tianhe
Zhang, Dongdong
Wang, Miao
Wu, Balu
Shang, Yufeng
Sattar, Safat
Ding, Lu
Liu, Yin
Jiang, Hongqiang
Liang, Yuxing
Zhou, Fuling
Wei, Yongchang
author_sort Yang, Tian
collection PubMed
description Radiotherapy is used to treat gastric cancer (GC); however, radioresistance challenges the clinical outcomes of GC, and the mechanisms of radioresistance in GC remain poorly understood. Here, we report that the TGF-β receptor inhibitor, LY2109761 (LY), is a potential radiosensitizer both in vitro and in vivo. As per the Cancer Genome Atlas database, TGF-β overexpression is significantly related to poor overall survival in GC patients. We demonstrated that the TGF-β/SMAD4 signaling pathway was activated in both radioresistant GC cells and radioresistant GC patients. As a TGF-β receptor inhibitor, LY can enhance the activities of irradiation by inhibiting cell proliferation, decreasing clonogenicity and increasing apoptosis. Moreover, LY attenuated the radiation-induced migration and invasion, epithelial-mesenchymal transition (EMT), inflammatory factor activation, immunosuppression, and cancer stem cell characteristics of GC cells, thus leading to radiosensitization of the GC cells. We confirmed that LY reduced tumor growth, inhibited TGF-β/SMAD4 pathway activation and reversed irradiation-induced EMT in a tumor xenograft model. Our findings indicate that the novel TGF-β receptor inhibitor, LY, increases GC radiosensitivity by directly regulating the TGF-β/SMAD4 signaling pathway. These findings provide new insight for radiotherapy in GC patients.
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spelling pubmed-68344152019-11-13 TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway Yang, Tian Huang, Tianhe Zhang, Dongdong Wang, Miao Wu, Balu Shang, Yufeng Sattar, Safat Ding, Lu Liu, Yin Jiang, Hongqiang Liang, Yuxing Zhou, Fuling Wei, Yongchang Aging (Albany NY) Research Paper Radiotherapy is used to treat gastric cancer (GC); however, radioresistance challenges the clinical outcomes of GC, and the mechanisms of radioresistance in GC remain poorly understood. Here, we report that the TGF-β receptor inhibitor, LY2109761 (LY), is a potential radiosensitizer both in vitro and in vivo. As per the Cancer Genome Atlas database, TGF-β overexpression is significantly related to poor overall survival in GC patients. We demonstrated that the TGF-β/SMAD4 signaling pathway was activated in both radioresistant GC cells and radioresistant GC patients. As a TGF-β receptor inhibitor, LY can enhance the activities of irradiation by inhibiting cell proliferation, decreasing clonogenicity and increasing apoptosis. Moreover, LY attenuated the radiation-induced migration and invasion, epithelial-mesenchymal transition (EMT), inflammatory factor activation, immunosuppression, and cancer stem cell characteristics of GC cells, thus leading to radiosensitization of the GC cells. We confirmed that LY reduced tumor growth, inhibited TGF-β/SMAD4 pathway activation and reversed irradiation-induced EMT in a tumor xenograft model. Our findings indicate that the novel TGF-β receptor inhibitor, LY, increases GC radiosensitivity by directly regulating the TGF-β/SMAD4 signaling pathway. These findings provide new insight for radiotherapy in GC patients. Impact Journals 2019-10-19 /pmc/articles/PMC6834415/ /pubmed/31631064 http://dx.doi.org/10.18632/aging.102329 Text en Copyright © 2019 Yang et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Yang, Tian
Huang, Tianhe
Zhang, Dongdong
Wang, Miao
Wu, Balu
Shang, Yufeng
Sattar, Safat
Ding, Lu
Liu, Yin
Jiang, Hongqiang
Liang, Yuxing
Zhou, Fuling
Wei, Yongchang
TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway
title TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway
title_full TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway
title_fullStr TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway
title_full_unstemmed TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway
title_short TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway
title_sort tgf-β receptor inhibitor ly2109761 enhances the radiosensitivity of gastric cancer by inactivating the tgf-β/smad4 signaling pathway
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834415/
https://www.ncbi.nlm.nih.gov/pubmed/31631064
http://dx.doi.org/10.18632/aging.102329
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