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Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling
Limited benefits and clinical utility of temozolomide (TMZ) for glioblastoma (GB) are frequently compromised by the development of acquired drug resistance. Overcoming TMZ resistance and uncovering the underlying mechanisms are challenges faced during GB chemotherapy. In this study, we reported that...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520906/ https://www.ncbi.nlm.nih.gov/pubmed/28617438 http://dx.doi.org/10.1038/cddis.2017.248 |
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author | Zeng, Huijun Yang, Zhao Xu, Ningbo Liu, Boyang Fu, Zhao Lian, Changlin Guo, Hongbo |
author_facet | Zeng, Huijun Yang, Zhao Xu, Ningbo Liu, Boyang Fu, Zhao Lian, Changlin Guo, Hongbo |
author_sort | Zeng, Huijun |
collection | PubMed |
description | Limited benefits and clinical utility of temozolomide (TMZ) for glioblastoma (GB) are frequently compromised by the development of acquired drug resistance. Overcoming TMZ resistance and uncovering the underlying mechanisms are challenges faced during GB chemotherapy. In this study, we reported that connective tissue growth factor (CTGF) was associated with GB chemoresistance and significantly upregulated in TMZ-treated GB cells. CTGF knockdown promoted TMZ-induced cell apoptosis and enhanced chemosensitivity, whereas its overexpression markedly conferred TMZ resistance in vitro and in vivo. Moreover, CTGF promoted TMZ resistance through stem-like properties acquisition and CD44 interference reversed the CTGF-induced TMZ resistance. Mechanistically, further investigation revealed that the TMZ-induced CTGF upregulation was tissue growth factor (TGF-β) dependent, and regulated by TGF-β1 activation through Smad and ERK1/2 signaling. Together, our results suggest a pivotal role of CTGF-mediated TMZ resistance through TGF-β1-dependent activation of Smad/ERK signaling pathways. These data provide us insights for identifying potential targets that are beneficial for overcoming TMZ resistance in GB. |
format | Online Article Text |
id | pubmed-5520906 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-55209062017-07-27 Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling Zeng, Huijun Yang, Zhao Xu, Ningbo Liu, Boyang Fu, Zhao Lian, Changlin Guo, Hongbo Cell Death Dis Original Article Limited benefits and clinical utility of temozolomide (TMZ) for glioblastoma (GB) are frequently compromised by the development of acquired drug resistance. Overcoming TMZ resistance and uncovering the underlying mechanisms are challenges faced during GB chemotherapy. In this study, we reported that connective tissue growth factor (CTGF) was associated with GB chemoresistance and significantly upregulated in TMZ-treated GB cells. CTGF knockdown promoted TMZ-induced cell apoptosis and enhanced chemosensitivity, whereas its overexpression markedly conferred TMZ resistance in vitro and in vivo. Moreover, CTGF promoted TMZ resistance through stem-like properties acquisition and CD44 interference reversed the CTGF-induced TMZ resistance. Mechanistically, further investigation revealed that the TMZ-induced CTGF upregulation was tissue growth factor (TGF-β) dependent, and regulated by TGF-β1 activation through Smad and ERK1/2 signaling. Together, our results suggest a pivotal role of CTGF-mediated TMZ resistance through TGF-β1-dependent activation of Smad/ERK signaling pathways. These data provide us insights for identifying potential targets that are beneficial for overcoming TMZ resistance in GB. Nature Publishing Group 2017-06 2017-06-15 /pmc/articles/PMC5520906/ /pubmed/28617438 http://dx.doi.org/10.1038/cddis.2017.248 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Zeng, Huijun Yang, Zhao Xu, Ningbo Liu, Boyang Fu, Zhao Lian, Changlin Guo, Hongbo Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling |
title | Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling |
title_full | Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling |
title_fullStr | Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling |
title_full_unstemmed | Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling |
title_short | Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-β1-dependent activation of Smad/ERK signaling |
title_sort | connective tissue growth factor promotes temozolomide resistance in glioblastoma through tgf-β1-dependent activation of smad/erk signaling |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520906/ https://www.ncbi.nlm.nih.gov/pubmed/28617438 http://dx.doi.org/10.1038/cddis.2017.248 |
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