This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pannequin, J. Articles by Hollande, F. Search for Related Content PubMed PubMed Citation Articles by Pannequin, J. Articles by Hollande, F.

---

DNA Damage and Cellular Stress Responses

Phosphatidylethanol Accumulation Promotes Intestinal Hyperplasia by Inducing ZONAB-Mediated Cell Density Increase in Response to Chronic Ethanol Exposure

¹ CNRS UMR5203; INSERM U661, University of Montpellier I, and University of Montpellier II, Cellular and Molecular Oncology Department, Institut de Génomique Fonctionnelle, Montpellier Cedex, France; ² INSERM U710; EPHE; Université de Montpellier II, F-34095, Montpellier, France; ³ Service d'Hépato-Gastroentérologie, CHU Carémeau, Nîmes, France; ⁴ Department of Pharmacology and Center for Developmental Genetics, Stony Brook University, New York, New York; and ⁵ Department of Cell Biology, University College London, London, United Kingdom

Requests for reprints: Frédéric Hollande, Laboratoire de Biochimie, Faculté de Pharmacie, Institut de Génomique Fonctionnelle, Bâtiment E, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France. Phone: 33-467-66-8144; Fax: 33-467-66-8144. E-mail: fhollande{at}univ-montp1.fr

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. (Mol Cancer Res 2007;5(11):1147–57)