Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells
- Date Crossref
- 01/08/2019
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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National Chiayi University Department of Biochemical Science and Technology pays non établi dans la noticeUniversité ou école supérieure
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Chiayi Chang Gung Memorial Hospital Department of Medical Research pays non établi dans la noticeÉtablissement de santé
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National Yang Ming Chiao Tung University pays non établi dans la noticeUniversité ou école supérieure
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University of Taipei Department of Earth and Life Sciences pays non établi dans la noticeUniversité ou école supérieure
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Chang Gung University of Science and Technology pays non établi dans la noticeUniversité ou école supérieure
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Chang Gung University pays non établi dans la noticeUniversité ou école supérieure
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National Yang-Ming University Department of Biotechnology and Laboratory Science in Medicine pays non établi dans la noticeUniversité ou école supérieure
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College of Medicine pays non établi dans la noticeUniversité ou école supérieure
Department of Biochemical Science and Technology — National Chiayi University, Department of Medical Research — Chiayi Chang Gung Memorial Hospital et National Yang Ming Chiao Tung University, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.