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Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells
BACKGROUND: Glioblastoma multiforme (GBM) is the most severe type of primary brain tumor with a high mortality rate. Although extensive treatments for GBM, including resection, irradiation, chemotherapy and immunotherapy, have been tried, the prognosis is still poor. Temozolomide (TMZ), an alkylatin...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670223/ https://www.ncbi.nlm.nih.gov/pubmed/31370819 http://dx.doi.org/10.1186/s12885-019-5843-6 |
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author | Chen, Jui-Chieh Lee, I-Neng Huang, Cheng Wu, Yu-Ping Chung, Chiu-Yen Lee, Ming-Hsueh Lin, Martin Hsiu-Chu Yang, Jen-Tsung |
author_facet | Chen, Jui-Chieh Lee, I-Neng Huang, Cheng Wu, Yu-Ping Chung, Chiu-Yen Lee, Ming-Hsueh Lin, Martin Hsiu-Chu Yang, Jen-Tsung |
author_sort | Chen, Jui-Chieh |
collection | PubMed |
description | BACKGROUND: Glioblastoma multiforme (GBM) is the most severe type of primary brain tumor with a high mortality rate. Although extensive treatments for GBM, including resection, irradiation, chemotherapy and immunotherapy, have been tried, the prognosis is still poor. Temozolomide (TMZ), an alkylating agent, is a front-line chemotherapeutic drug for the clinical treatment of GBM; however, its effects are very limited because of the chemoresistance. Valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitor activity, has been shown to have synergistic effects with TMZ against GBM. The mechanism of action of VPA on TMZ combination therapy is still unclear. Accumulating evidence has shown that secreted proteins are responsible for the cross talking among cells in the tumor microenvironment, which may play a critical role in the regulation of drug responses. METHODS: To understand the effect of VPA on secreted proteins in GBM cells, we first used the antibody array to analyze the cell culture supernatant from VPA-treated and untreated GBM cells. The results were further confirmed by lentivirus-mediated knockdown and exogenous recombinant administration. RESULTS: Our results showed that amphiregulin (AR) was highly secreted in VPA-treated cells. Knockdown of AR can sensitize GBM cells to TMZ. Furthermore, pretreatment of exogenous recombinant AR significantly increased EGFR activation and conferred resistance to TMZ. To further verify the effect of AR on TMZ resistance, cells pre-treated with AR neutralizing antibody markedly increased sensitivity to TMZ. In addition, we also observed that the expression of AR was positively correlated with the resistance of TMZ in different GBM cell lines. CONCLUSIONS: The present study aimed to identify the secreted proteins that contribute to the modulation of drug response. Understanding the full set of secreted proteins present in glial cells might help reveal potential therapeutic opportunities. The results indicated that AR may potentially serve as biomarker and therapeutic approach for chemotherapy regimens in GBM. |
format | Online Article Text |
id | pubmed-6670223 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-66702232019-08-06 Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells Chen, Jui-Chieh Lee, I-Neng Huang, Cheng Wu, Yu-Ping Chung, Chiu-Yen Lee, Ming-Hsueh Lin, Martin Hsiu-Chu Yang, Jen-Tsung BMC Cancer Research Article BACKGROUND: Glioblastoma multiforme (GBM) is the most severe type of primary brain tumor with a high mortality rate. Although extensive treatments for GBM, including resection, irradiation, chemotherapy and immunotherapy, have been tried, the prognosis is still poor. Temozolomide (TMZ), an alkylating agent, is a front-line chemotherapeutic drug for the clinical treatment of GBM; however, its effects are very limited because of the chemoresistance. Valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitor activity, has been shown to have synergistic effects with TMZ against GBM. The mechanism of action of VPA on TMZ combination therapy is still unclear. Accumulating evidence has shown that secreted proteins are responsible for the cross talking among cells in the tumor microenvironment, which may play a critical role in the regulation of drug responses. METHODS: To understand the effect of VPA on secreted proteins in GBM cells, we first used the antibody array to analyze the cell culture supernatant from VPA-treated and untreated GBM cells. The results were further confirmed by lentivirus-mediated knockdown and exogenous recombinant administration. RESULTS: Our results showed that amphiregulin (AR) was highly secreted in VPA-treated cells. Knockdown of AR can sensitize GBM cells to TMZ. Furthermore, pretreatment of exogenous recombinant AR significantly increased EGFR activation and conferred resistance to TMZ. To further verify the effect of AR on TMZ resistance, cells pre-treated with AR neutralizing antibody markedly increased sensitivity to TMZ. In addition, we also observed that the expression of AR was positively correlated with the resistance of TMZ in different GBM cell lines. CONCLUSIONS: The present study aimed to identify the secreted proteins that contribute to the modulation of drug response. Understanding the full set of secreted proteins present in glial cells might help reveal potential therapeutic opportunities. The results indicated that AR may potentially serve as biomarker and therapeutic approach for chemotherapy regimens in GBM. BioMed Central 2019-08-01 /pmc/articles/PMC6670223/ /pubmed/31370819 http://dx.doi.org/10.1186/s12885-019-5843-6 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Chen, Jui-Chieh Lee, I-Neng Huang, Cheng Wu, Yu-Ping Chung, Chiu-Yen Lee, Ming-Hsueh Lin, Martin Hsiu-Chu Yang, Jen-Tsung Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells |
title | Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells |
title_full | Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells |
title_fullStr | Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells |
title_full_unstemmed | Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells |
title_short | Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells |
title_sort | valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670223/ https://www.ncbi.nlm.nih.gov/pubmed/31370819 http://dx.doi.org/10.1186/s12885-019-5843-6 |
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