Format

Send to

Choose Destination
Cancers (Basel). 2019 Jun 30;11(7). pii: E921. doi: 10.3390/cancers11070921.

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.

Author information

1
Department of Neurosurgery, UKGM, Philipps University Marburg, Baldingerstraße, 35033 Marburg, Germany.
2
Department of Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
3
Department of Neuropathology, UKGM, Philipps University Marburg, Baldingerstraße, 35033 Marburg, Germany.
4
Genomics Core Facility, Philipps University Marburg, Hans-Meerwein-Straße 3, 35043 Marburg, Germany.
5
Institute of Molecular Oncology, member of the German Center for Lung Research (DZL), Philipps University Marburg, Hans-Meerwein-Straße 3, 35043 Marburg, Germany.
6
Institute for Neuropathology, Justus-Liebig University Gießen, Arndtstr. 16, 35392 Gießen, Germany.
7
Department of Neurosurgery, UKGM, Philipps University Marburg, Baldingerstraße, 35033 Marburg, Germany. jbartsch@med.uni-marburg.de.

Abstract

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.

KEYWORDS:

GBM Stem-like cells; GBM recurrence; acetazolamide; carbonic anhydrase 2; chemoresistance; glioblastoma; temozolomide; transcriptomics

PMID:
31262047
DOI:
10.3390/cancers11070921
Free full text

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI)
Loading ...
Support Center