Document Detail


Cell cycle control pathways act as conditioning factors for TK/GCV sensitivity in pancreatic cancer cells.
MedLine Citation:
PMID:  20599444     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The suicide system TK/GCV is an enzyme/prodrug therapy that involves the transfer of the cDNA for the herpes simplex virus thymidine kinase gene (TK) into tumor cells which then sensitizes the cells to the non-toxic antiviral drug ganciclovir. Although extensively characterized, the suicide system TK/GCV conceals the details of its mechanism of action. In order to shed some light on this issue, we conducted experiments designed to identify key features of sensitive cells, as compared to cells that displayed reduced sensitivity to TK/GCV. Cell lines displaying different degrees of sensitivity underwent apoptotic cell death upon treatment with TK/GCV. S-phase delay, however, was almost exclusively restricted to sensitive cells and was impaired in a model of treatment-induced resistance. In this model genes with differential expression associated to induced resistance were identified. Noteworthy, two cell cycle-related genes (CCNE1 and GADD45) were functionally validated as conditioners of cellular sensitivity to TK/GCV. The relevance of cell cycle control was further demonstrated by experiments showing the association of Chk1 activation with greater TK/GCV cytotoxicity. Combination treatment with Chk1 inhibitor UCN-01 induced, in sensitive cells, an antagonistic effect on TK/GCV cytotoxicity highlighting the relevance of Chk1's activity on TK/GCV mechanism of action. These results reveal the relevance of cell cycle control pathways in the cytotoxicity induced by the TK/GCV system identifying candidate genes as conditioners of TK/GCV sensitivity. Moreover it points out, for the first time at Chk1 activation as a key factor to mediate TK/GCV cytotoxicity.
Authors:
Daniel Abate-Daga; Laura Garcia-Rodríguez; Lauro Sumoy; Cristina Fillat
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-03
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1803     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-08-16     Completed Date:  2010-10-28     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1175-85     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier B.V. All rights reserved.
Affiliation:
Programa Gens i Malaltia, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
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MeSH Terms
Descriptor/Qualifier:
Antiviral Agents / pharmacology
Apoptosis / drug effects
Blotting, Western
Cell Cycle / drug effects,  physiology*
Cell Cycle Proteins / genetics,  metabolism
Cell Line, Tumor
Cell Survival / drug effects
Cyclin E / genetics,  metabolism
DNA-Binding Proteins / genetics,  metabolism
Ganciclovir / pharmacology*
Gene Expression Profiling
Humans
Nuclear Proteins / genetics,  metabolism
Oligonucleotide Array Sequence Analysis
Oncogene Proteins / genetics,  metabolism
Pancreatic Neoplasms / genetics,  metabolism,  pathology
Protein Kinases / genetics,  metabolism
Protein-Serine-Threonine Kinases / genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects,  physiology*
Thymidine Kinase / genetics,  metabolism*
Time Factors
Tumor Suppressor Proteins / genetics,  metabolism
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/CCNE1 protein, human; 0/Cell Cycle Proteins; 0/Cyclin E; 0/DNA-Binding Proteins; 0/GADD45A protein, human; 0/Nuclear Proteins; 0/Oncogene Proteins; 0/Tumor Suppressor Proteins; 82410-32-0/Ganciclovir; EC 2.7.-/Protein Kinases; EC 2.7.1.-/ATR protein, human; EC 2.7.1.11/checkpoint kinase 2; EC 2.7.1.21/Thymidine Kinase; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein

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


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