Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy.

Détails

ID Serval
serval:BIB_0B6F8DAAB549
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy.
Périodique
Cancer Research
Auteur(s)
Apel A., Herr I., Schwarz H., Rodemann H.P., Mayer A.
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Statut éditorial
Publié
Date de publication
2008
Volume
68
Numéro
5
Pages
1485-1494
Langue
anglais
Résumé
Autophagy or "self eating" is frequently activated in tumor cells treated with chemotherapy or irradiation. Whether autophagy represents a survival mechanism or rather contributes to cell death remains controversial. To address this issue, the role of autophagy in radiosensitive and radioresistant human cancer cell lines in response to gamma-irradiation was examined. We found irradiation-induced accumulation of autophagosomes accompanied by strong mRNA induction of the autophagy-related genes beclin 1, atg3, atg4b, atg4c, atg5, and atg12 in each cell line. Transduction of specific target-siRNAs led to down-regulation of these genes for up to 8 days as shown by reverse transcription-PCR and Western blot analysis. Blockade of each autophagy-related gene was associated with strongly diminished accumulation of autophagosomes after irradiation. As shown by clonogenic survival, the majority of inhibited autophagy-related genes, each alone or combined, resulted in sensitization of resistant carcinoma cells to radiation, whereas untreated resistant cells but not sensitive cells survived better when autophagy was inhibited. Similarly, radiosensitization or the opposite was observed in different sensitive carcinoma cells and upon inhibition of different autophagy genes. Mutant p53 had no effect on accumulation of autophagosomes but slightly increased clonogenic survival, as expected, because mutated p53 protects cells by conferring resistance to apoptosis. In our system, short-time inhibition of autophagy along with radiotherapy lead to enhanced cytotoxicity of radiotherapy in resistant cancer cells.
Mots-clé
Apoptosis, Autophagy, Carcinoma/pathology, Carcinoma/radiotherapy, Cell Line, Tumor, Cell Survival, Genes, p53, Humans, Models, Biological, Models, Genetic, Mutation, Neoplasms/genetics, Neoplasms/radiotherapy, RNA, Small Interfering/metabolism, Radiation Tolerance, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Protein p53/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/03/2009 14:51
Dernière modification de la notice
08/05/2019 14:16
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