| Three-dimensional cell growth confers radioresistance by chromatin density modification. | |
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MedLine Citation:
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PMID: 20442295 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cell shape and architecture are determined by cell-extracellular matrix interactions and have profound effects on cellular behavior, chromatin condensation, and tumor cell resistance to radiotherapy and chemotherapy. To evaluate the role of chromatin condensation for radiation cell survival, tumor cells grown in three-dimensional (3D) cell cultures as xenografts and monolayer cell cultures were compared. Here, we show that increased levels of heterochromatin in 3D cell cultures characterized by histone H3 deacetylation and induced heterochromatin protein 1alpha expression result in increased radiation survival and reduced numbers of DNA double strand breaks (DSB) and lethal chromosome aberrations. Intriguingly, euchromatin to heterochromatin-associated DSBs were equally distributed in irradiated 3D cell cultures and xenograft tumors, whereas irradiated monolayer cultures showed a 2:1 euchromatin to heterochromatin DSB distribution. Depletion of histone deacetylase (HDAC) 1/2/4 or application of the class I/II pharmacologic HDAC inhibitor LBH589 induced moderate or strong chromatin decondensation, respectively, which was translated into cell line-dependent radiosensitization and, in case of LBH589, into an increased number of DSBs. Neither growth conditions nor HDAC modifications significantly affected the radiation-induced phosphorylation of the important DNA repair protein ataxia telangiectasia mutated. Our data show an interrelation between cell morphology and cellular radiosensitivity essentially based on chromatin organization. Understanding the molecular mechanisms by which chromatin structure influences the processing of radiation-induced DNA lesions is of high relevance for normal tissue protection and optimization of cancer therapy. |
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Authors:
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Katja Storch; Iris Eke; Kerstin Borgmann; Mechthild Krause; Christian Richter; Kerstin Becker; Evelin Schröck; Nils Cordes |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-04 |
Journal Detail:
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Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-14 Completed Date: 2010-06-21 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3925-34 Citation Subset: IM |
Copyright Information:
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(c)2010 AACR. |
Affiliation:
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OncoRay-Center for Radiation Research in Oncology, Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western Carcinoma, Squamous Cell / metabolism, pathology Cell Culture Techniques Cell Cycle Proteins / metabolism Cell Shape Chromosomal Proteins, Non-Histone / metabolism Chromosome Aberrations* DNA Breaks, Double-Stranded / radiation effects DNA Repair DNA-Binding Proteins / metabolism Euchromatin / physiology* Female Fluorescent Antibody Technique Gamma Rays Head and Neck Neoplasms / metabolism, pathology* Heterochromatin / physiology* Histone Deacetylases / chemistry, metabolism Histones / metabolism Humans Lung Neoplasms / genetics, metabolism, pathology* Male Mice Mice, Nude Protein-Serine-Threonine Kinases / metabolism Radiation Tolerance Tumor Cells, Cultured Tumor Suppressor Proteins / metabolism Xenograft Model Antitumor Assays |
| Chemical | |
Reg. No./Substance:
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0/Cell Cycle Proteins; 0/Chromosomal Proteins, Non-Histone; 0/DNA-Binding Proteins; 0/Euchromatin; 0/Heterochromatin; 0/Histones; 0/Tumor Suppressor Proteins; 107283-02-3/heterochromatin-specific nonhistone chromosomal protein HP-1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein; EC 3.5.1.98/Histone Deacetylases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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