Alpha-6 integrin promotes radioresistance of glioblastoma by modulating DNA damage response and the transcription factor Zeb1.
Cell Death Dis
; 9(9): 872, 2018 08 29.
Article
em En
| MEDLINE
| ID: mdl-30158599
ABSTRACT
Radiotherapy is the cornerstone of glioblastoma (GBM) standard treatment. However, radioresistance of cancer cells leads to an inevitable recurrence. In the present study, we showed that blocking α6-integrin in cells derived from GBM biopsy specimens cultured as neurospheres, sensitized cells to radiation. In cells downregulated for α6-integrin expression, we observed a decrease in cell survival after irradiation and an increase in radio-induced cell death. We also demonstrated that inhibition of α6-integrin expression affects DNA damage checkpoint and repair. Indeed, we observed a persistence of γ-H2AX staining after IR and the abrogation of the DNA damage-induced G2/M checkpoint, likely through the downregulation of the checkpoint kinase CHK1 and its downstream target Cdc25c. We also showed that α6-integrin contributes to GBM radioresistance by controlling the expression of the transcriptional network ZEB1/OLIG2/SOX2. Finally, the clinical data from TCGA and Rembrandt databases demonstrate that GBM patients with high levels of the five genes signature, including α6-integrin and its targets, CHK1, ZEB1, OLIG2 and SOX2, have a significantly shorter overall survival. Our study suggest that α6-integrin is an attractive therapeutic target to overcome radioresistance of GBM cancer cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tolerância a Radiação
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Dano ao DNA
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Neoplasias Encefálicas
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Glioblastoma
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Cadeias alfa de Integrinas
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Homeobox 1 de Ligação a E-box em Dedo de Zinco
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article