Document Detail


Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy.
MedLine Citation:
PMID:  18316613     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Anja Apel; Ingrid Herr; Heinz Schwarz; H Peter Rodemann; Andreas Mayer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  68     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-04     Completed Date:  2008-04-08     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1485-94     Citation Subset:  IM    
Affiliation:
Division of Radiobiology and Molecular Environmental Research, University of Tuebingen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis
Autophagy*
Carcinoma / pathology*,  radiotherapy*
Cell Line, Tumor
Cell Survival
Genes, p53
Humans
Models, Biological
Models, Genetic
Mutation
Neoplasms / genetics*,  radiotherapy*
RNA, Small Interfering / metabolism
Radiation Tolerance*
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Protein p53 / metabolism
Chemical
Reg. No./Substance:
0/RNA, Small Interfering; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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