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Abrogation of radioresistance in glioblastoma stem-like cells by inhibition of ATM kinase.
- Source :
-
Molecular oncology [Mol Oncol] 2015 Jan; Vol. 9 (1), pp. 192-203. Date of Electronic Publication: 2014 Aug 24. - Publication Year :
- 2015
-
Abstract
- Resistance to radiotherapy in glioblastoma (GBM) is an important clinical problem and several authors have attributed this to a subpopulation of GBM cancer stem cells (CSCs) which may be responsible for tumour recurrence following treatment. It is hypothesised that GBM CSCs exhibit upregulated DNA damage responses and are resistant to radiation but the current literature is conflicting. We investigated radioresistance of primary GBM cells grown in stem cell conditions (CSC) compared to paired differentiated tumour cell populations and explored the radiosensitising effects of the ATM inhibitor KU-55933. We report that GBM CSCs are radioresistant compared to paired differentiated tumour cells as measured by clonogenic assay. GBM CSC's display upregulated phosphorylated DNA damage response proteins and enhanced activation of the G2/M checkpoint following irradiation and repair DNA double strand breaks (DSBs) more efficiently than their differentiated tumour cell counterparts following radiation. Inhibition of ATM kinase by KU-55933 produced potent radiosensitisation of GBM CSCs (sensitiser enhancement ratios 2.6-3.5) and effectively abrogated the enhanced DSB repair proficiency observed in GBM CSCs at 24 h post irradiation. G2/M checkpoint activation was reduced but not abolished by KU-55933 in GBM CSCs. ATM kinase inhibition overcomes radioresistance of GBM CSCs and, in combination with conventional therapy, has potential to improve outcomes for patients with GBM.<br /> (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Ataxia Telangiectasia Mutated Proteins metabolism
Female
G2 Phase Cell Cycle Checkpoints drug effects
G2 Phase Cell Cycle Checkpoints radiation effects
Gamma Rays
Glioblastoma enzymology
Glioblastoma pathology
Humans
M Phase Cell Cycle Checkpoints drug effects
M Phase Cell Cycle Checkpoints radiation effects
Male
Neoplasm Proteins metabolism
Neoplastic Stem Cells pathology
Radiation Tolerance radiation effects
Tumor Cells, Cultured
Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors
Glioblastoma radiotherapy
Morpholines pharmacology
Neoplasm Proteins antagonists & inhibitors
Neoplastic Stem Cells enzymology
Pyrones pharmacology
Radiation Tolerance drug effects
Radiation-Sensitizing Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 25205037
- Full Text :
- https://doi.org/10.1016/j.molonc.2014.08.003