Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation

Preclinical data have revealed the inhibitory effect of dasatinib on colon cancer. However, a combination of dasatinib and conventional chemotherapy has failed to show any meaningful outcome in a series of clinical trials. We, therefore, wondered whether Src kinase inhibitors were suitable for treat...

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Autores principales: Fu, Yang, Yang, Ge, Xue, Peipei, Guo, Luwei, Yin, Yuhan, Ye, Zhiqiang, Peng, Sanfei, Qin, Yanru, Duan, Qiuhong, Zhu, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966379/
https://www.ncbi.nlm.nih.gov/pubmed/29844931
http://dx.doi.org/10.1038/s41420-018-0062-5
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author Fu, Yang
Yang, Ge
Xue, Peipei
Guo, Luwei
Yin, Yuhan
Ye, Zhiqiang
Peng, Sanfei
Qin, Yanru
Duan, Qiuhong
Zhu, Feng
author_facet Fu, Yang
Yang, Ge
Xue, Peipei
Guo, Luwei
Yin, Yuhan
Ye, Zhiqiang
Peng, Sanfei
Qin, Yanru
Duan, Qiuhong
Zhu, Feng
author_sort Fu, Yang
collection PubMed
description Preclinical data have revealed the inhibitory effect of dasatinib on colon cancer. However, a combination of dasatinib and conventional chemotherapy has failed to show any meaningful outcome in a series of clinical trials. We, therefore, wondered whether Src kinase inhibitors were suitable for treating colon cancer in combination with chemotherapy drugs. This study was designed to explore whether dasatinib disturbed 5-Fu-triggered apoptosis in colon carcinoma. As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity. Dasatinib dramatically decreased 5-Fu triggered apoptosis in colon carcinoma via suppression of Src activation. Our findings may have partially explained why dasatinib combined with FOLFOX failed to show a meaningful clinical response in mCRC.
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spelling pubmed-59663792018-05-29 Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation Fu, Yang Yang, Ge Xue, Peipei Guo, Luwei Yin, Yuhan Ye, Zhiqiang Peng, Sanfei Qin, Yanru Duan, Qiuhong Zhu, Feng Cell Death Discov Article Preclinical data have revealed the inhibitory effect of dasatinib on colon cancer. However, a combination of dasatinib and conventional chemotherapy has failed to show any meaningful outcome in a series of clinical trials. We, therefore, wondered whether Src kinase inhibitors were suitable for treating colon cancer in combination with chemotherapy drugs. This study was designed to explore whether dasatinib disturbed 5-Fu-triggered apoptosis in colon carcinoma. As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity. Dasatinib dramatically decreased 5-Fu triggered apoptosis in colon carcinoma via suppression of Src activation. Our findings may have partially explained why dasatinib combined with FOLFOX failed to show a meaningful clinical response in mCRC. Nature Publishing Group UK 2018-05-23 /pmc/articles/PMC5966379/ /pubmed/29844931 http://dx.doi.org/10.1038/s41420-018-0062-5 Text en © The Author(s) 2018 Open Access 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 http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Fu, Yang
Yang, Ge
Xue, Peipei
Guo, Luwei
Yin, Yuhan
Ye, Zhiqiang
Peng, Sanfei
Qin, Yanru
Duan, Qiuhong
Zhu, Feng
Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation
title Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation
title_full Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation
title_fullStr Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation
title_full_unstemmed Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation
title_short Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation
title_sort dasatinib reduces 5-fu-triggered apoptosis in colon carcinoma by directly modulating src-dependent caspase-9 phosphorylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966379/
https://www.ncbi.nlm.nih.gov/pubmed/29844931
http://dx.doi.org/10.1038/s41420-018-0062-5
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