| TRAIL treatment provokes mutations in surviving cells. | |
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MedLine Citation:
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PMID: 20639907 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Chemotherapy and radiotherapy commonly damage DNA and trigger p53-dependent apoptosis through intrinsic apoptotic pathways. Two unfortunate consequences of this mechanism are resistance due to blockade of p53 or intrinsic apoptosis pathways, and mutagenesis of non-malignant surviving cells which can impair cellular function or provoke second malignancies. Death ligand-based drugs, such as tumor necrosis factor-related apoptosis inducing ligand (TRAIL), stimulate extrinsic apoptotic signaling, and may overcome resistance to treatments that induce intrinsic apoptosis. As death receptor ligation does not damage DNA as a primary mechanism of pro-apoptotic action, we hypothesized that surviving cells would remain genetically unscathed, suggesting that death ligand-based therapies may avoid some of the adverse effects associated with traditional cancer treatments. Surprisingly, however, treatment with sub-lethal concentrations of TRAIL or FasL was mutagenic. Mutations arose in viable cells that contained active caspases, and overexpression of the caspase-8 inhibitor crmA or silencing of caspase-8 abolished TRAIL-mediated mutagenesis. Downregulation of the apoptotic nuclease caspase-activated DNAse (CAD)/DNA fragmentation factor 40 (DFF40) prevented the DNA damage associated with TRAIL treatment. Although death ligands do not need to damage DNA in order to induce apoptosis, surviving cells nevertheless incur DNA damage after treatment with these agents. |
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Authors:
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M M Lovric; C J Hawkins |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-19 |
Journal Detail:
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Title: Oncogene Volume: 29 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-09 Completed Date: 2010-09-17 Revised Date: 2010-12-20 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 5048-60 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, Victoria, Australia. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / pharmacology Cell Line, Tumor Cell Survival / drug effects, genetics Cells, Cultured Cisplatin / pharmacology Deoxyribonucleases / antagonists & inhibitors, genetics, metabolism Drug Resistance, Neoplasm / drug effects*, genetics Fibroblasts / drug effects, metabolism Mice Models, Biological Mutation* / drug effects Neoplasms / genetics, metabolism, pathology* RNA, Small Interfering / pharmacology TNF-Related Apoptosis-Inducing Ligand / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/RNA, Small Interfering; 0/TNF-Related Apoptosis-Inducing Ligand; 15663-27-1/Cisplatin; EC 3.1.-/Deoxyribonucleases; EC 3.1.-/caspase-activated deoxyribonuclease |
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