Hannen, R.* ; Selmansberger, M. ; Hauswald, M.* ; Pagenstecher, A.* ; Nist, A.* ; Stiewe, T.* ; Acker, T.* ; Carl, B.* ; Nimsky, C.* ; Bartsch, J.W.*
Comparative transcriptomic analysis of temozolomide resistant primary GBM stem-like cells and recurrent GBM identifies up-regulation of the carbonic anhydrase CA2 gene as resistance factor.
Cancers 11:921 (2019)
About 95% of patients with Glioblastoma (GBM) show tumor relapse, leaving them with limited therapeutic options as recurrent tumors are most often resistant to the first line chemotherapy standard Temozolomide (TMZ). To identify molecular pathways involved in TMZ resistance, primary GBM Stem-like Cells (GSCs) were isolated, characterized, and selected for TMZ resistance in vitro. Subsequently, RNA sequencing analysis was performed and revealed a total of 49 differentially expressed genes (|log2-fold change| > 0.5 and adjusted p-value < 0.1) in TMZ resistant stem-like cells compared to their matched DMSO control cells. Among up-regulated genes, we identified carbonic anhydrase 2 (CA2) as a candidate gene correlated with glioma malignancy and patient survival. Notably, we describe consistent up-regulation of CA2 not only in TMZ resistant GSCs on mRNA and protein level, but also in patient-matched clinical samples of first manifest and recurrent tumors. Co-treatment with the carbonic anhydrase inhibitor Acetazolamid (ACZ) sensitized cells to TMZ induced cell death. Cumulatively, our findings illustrate the potential of CA2 as a chemosensitizing target in recurrent GBM and provide a rationale for a therapy associated inhibition of CA2 to overcome TMZ induced chemoresistance.
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Publication type
Article: Journal article
Document type
Scientific Article
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Keywords
Glioblastoma ; Gbm Stem-like Cells ; Temozolomide ; Chemoresistance ; Gbm Recurrence ; Transcriptomics ; Acetazolamide ; Carbonic Anhydrase 2; Msh6 Mutations; Glioblastoma; Evolution; Radiotherapy; Therapy; Gliomas; Ix
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Language
english
Publication Year
2019
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2019
ISSN (print) / ISBN
2072-6694
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Volume: 11,
Issue: 7,
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Article Number: 921
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MDPI
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St Alban-anlage 66, Ch-4052 Basel, Switzerland
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Peer reviewed
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Radiation Sciences
PSP Element(s)
G-501000-001
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Erfassungsdatum
2019-07-30