Document Detail

Three-dimensional cell growth confers radioresistance by chromatin density modification.
MedLine Citation:
PMID:  20442295     Owner:  NLM     Status:  MEDLINE    
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.
Katja Storch; Iris Eke; Kerstin Borgmann; Mechthild Krause; Christian Richter; Kerstin Becker; Evelin Schröck; Nils Cordes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-04
Journal Detail:
Title:  Cancer research     Volume:  70     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-14     Completed Date:  2010-06-21     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3925-34     Citation Subset:  IM    
Copyright Information:
(c)2010 AACR.
OncoRay-Center for Radiation Research in Oncology, Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
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MeSH Terms
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*
Fluorescent Antibody Technique
Gamma Rays
Head and Neck Neoplasms / metabolism,  pathology*
Heterochromatin / physiology*
Histone Deacetylases / chemistry,  metabolism
Histones / metabolism
Lung Neoplasms / genetics,  metabolism,  pathology*
Mice, Nude
Protein-Serine-Threonine Kinases / metabolism
Radiation Tolerance
Tumor Cells, Cultured
Tumor Suppressor Proteins / metabolism
Xenograft Model Antitumor Assays
Reg. No./Substance:
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 Kinases; EC telangiectasia mutated protein; EC Deacetylases

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

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