Document Detail

Phosphatidylethanol accumulation promotes intestinal hyperplasia by inducing ZONAB-mediated cell density increase in response to chronic ethanol exposure.
MedLine Citation:
PMID:  18025260     Owner:  NLM     Status:  MEDLINE    
Chronic alcohol consumption is associated with increased risk of gastrointestinal cancer. High concentrations of ethanol trigger mucosal hyperregeneration, disrupt cell adhesion, and increase the sensitivity to carcinogens. Most of these effects are thought to be mediated by acetaldehyde, a genotoxic metabolite produced from ethanol by alcohol dehydrogenases. Here, we studied the role of low ethanol concentrations, more likely to mimic those found in the intestine in vivo, and used intestinal cells lacking alcohol dehydrogenase to identify the acetaldehyde-independent biological effects of ethanol. Under these conditions, ethanol did not stimulate the proliferation of nonconfluent cells, but significantly increased maximal cell density. Incorporation of phosphatidylethanol, produced from ethanol by phospholipase D, was instrumental to this effect. Phosphatidylethanol accumulation induced claudin-1 endocytosis and disrupted the claudin-1/ZO-1 association. The resulting nuclear translocation of ZONAB was shown to mediate the cell density increase in ethanol-treated cells. In vivo, incorporation of phosphatidylethanol and nuclear translocation of ZONAB correlated with increased proliferation in the colonic epithelium of ethanol-fed mice and in adenomas of chronic alcoholics. Our results show that phosphatidylethanol accumulation after chronic ethanol exposure disrupts signals that normally restrict proliferation in highly confluent intestinal cells, thus facilitating abnormal intestinal cell proliferation.
Julie Pannequin; Nathalie Delaunay; Charbel Darido; Tangui Maurice; Philippe Crespy; Michael A Frohman; Maria S Balda; Karl Matter; Dominique Joubert; Jean-François Bourgaux; Jean-Pierre Bali; Frédéric Hollande
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  5     ISSN:  1541-7786     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2007 Nov 
Date Detail:
Created Date:  2007-11-20     Completed Date:  2008-01-23     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1147-57     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Adenocarcinoma / chemically induced*,  metabolism
Alcohol Dehydrogenase / deficiency,  genetics
CCAAT-Enhancer-Binding Proteins / genetics,  metabolism*
Caco-2 Cells
Cell Count
Colonic Neoplasms / chemically induced*,  metabolism
Ethanol / toxicity*
Glycerophospholipids / metabolism*
Heat-Shock Proteins / genetics,  metabolism*
Hyperplasia / chemically induced
Intestines / drug effects*,  pathology*
Membrane Proteins / metabolism
Phospholipase D / metabolism
Phosphoproteins / metabolism
Zonula Occludens-1 Protein
Grant Support
G0400678//Medical Research Council
Reg. No./Substance:
0/CCAAT-Enhancer-Binding Proteins; 0/CLDN1 protein, human; 0/CSDA protein, human; 0/Claudin-1; 0/Cldn1 protein, mouse; 0/Glycerophospholipids; 0/Heat-Shock Proteins; 0/Membrane Proteins; 0/Phosphoproteins; 0/TJP1 protein, human; 0/Tjp1 protein, mouse; 0/Zonula Occludens-1 Protein; 0/phosphatidylethanol; 3K9958V90M/Ethanol; EC Dehydrogenase; EC D

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

Previous Document:  Cyclin-dependent kinase inhibitors sensitize tumor cells to nutlin-induced apoptosis: a potent drug ...
Next Document:  Molecular mechanisms of liver carcinogenesis in the mdr2-knockout mice.