Document Detail


5-ASA affects cell cycle progression in colorectal cells by reversibly activating a replication checkpoint.
MedLine Citation:
PMID:  17241873     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Individuals with inflammatory bowel disease are at risk of developing colorectal cancer (CRC). Epidemiologic, animal, and laboratory studies suggest that 5-amino-salicylic acid (5-ASA) protects from the development of CRC by altering cell cycle progression and by inducing apoptosis. Our previous results indicate that 5-ASA improves replication fidelity in colorectal cells, an effect that is active in reducing mutations. In this study, we hypothesized that 5-ASA restrains cell cycle progression by activating checkpoint pathways in colorectal cell lines, which would prevent tumor development and improve genomic stability.
METHODS: CRC cells with different genetic backgrounds such as HT29, HCT116, HCT116(p53-/-), HCT116+chr3, and LoVo were treated with 5-ASA for 2-96 hours. Cell cycle progression, phosphorylation, and DNA binding of cell cycle checkpoint proteins were analyzed.
RESULTS: We found that 5-ASA at concentrations between 10 and 40 mmol/L affects cell cycle progression by inducing cells to accumulate in the S phase. This effect was independent of the hMLH1, hMSH2, and p53 status because it was observed to a similar extent in all cell lines under investigation. Moreover, wash-out experiments demonstrated reversibility within 48 hours. Although p53 did not have a causative role, p53 Ser15 was strongly phosphorylated. Proteins involved in the ATM-and-Rad3-related kinase (ATR)-dependent S-phase checkpoint response (Chk1 and Rad17) were also phosphorylated but not ataxia telengectasia mutated kinase.
CONCLUSIONS: Our data demonstrate that 5-ASA causes cells to reversibly accumulate in S phase and activate an ATR-dependent checkpoint. The activation of replication checkpoint may slow down DNA replication and improve DNA replication fidelity, which increases the maintenance of genomic stability and counteracts carcinogenesis.
Authors:
M Gloria Luciani; Christoph Campregher; John M Fortune; Thomas A Kunkel; Christoph Gasche
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2006-10-12
Journal Detail:
Title:  Gastroenterology     Volume:  132     ISSN:  0016-5085     ISO Abbreviation:  Gastroenterology     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-01-23     Completed Date:  2007-03-14     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  221-35     Citation Subset:  AIM; IM    
Affiliation:
Medical University of Vienna, Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Währinger Gürtel 18, A-1090 Vienna, Austria.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / metabolism
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Apoptosis / drug effects
Carrier Proteins / genetics,  metabolism
Cell Cycle / drug effects
Cell Cycle Proteins / metabolism
Cell Division / drug effects
Colorectal Neoplasms / pathology,  prevention & control*
DNA Mismatch Repair / drug effects
DNA Polymerase III / metabolism
DNA Replication / drug effects*,  physiology
DNA-Binding Proteins / metabolism
Flow Cytometry
HT29 Cells
Humans
Mesalamine / pharmacology*
Mitosis / drug effects
Nuclear Proteins / genetics,  metabolism
Protein Kinases / metabolism
Protein-Serine-Threonine Kinases / metabolism
S Phase / drug effects
Tumor Suppressor Protein p53 / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
P 18270-B14//Austrian Science Fund FWF
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/CDC45 protein, human; 0/CLSPN protein, human; 0/Carrier Proteins; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/MCM2 protein, human; 0/MCM7 protein, human; 0/MLH1 protein, human; 0/Nuclear Proteins; 0/Rad17 protein, human; 0/Tumor Suppressor Protein p53; 89-57-6/Mesalamine; EC 2.7.-/Protein Kinases; EC 2.7.1.-/ATR protein, human; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.7.-/DNA Polymerase III
Comments/Corrections
Comment In:
Gastroenterology. 2007 Apr;132(4):1635-6; author reply 1636   [PMID:  17418160 ]

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