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Infection and Immunity, September 2000, p. 5321-5328, Vol. 68, No. 9
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Chronic Helicobacter pylori Infection Induces an Apoptosis-Resistant Phenotype Associated with Decreased Expression of p27kip1

Haim Shirin,1,2,dagger Emilia Mia Sordillo,1,3 Tatiana K. Kolevska,1 Hanina Hibshoosh,4 Yuichi Kawabata,2 Sung H. Oh,1 Joachim F. Kuebler,1 Thomas Delohery,5 Christopher M. Weghorst,6 I. Bernard Weinstein,2 and Steven F. Moss1,*

Departments of Medicine1 and of Pathology and Laboratory Medicine,3 St. Luke's-Roosevelt Hospital Center, and Herbert Irving Comprehensive Cancer Center2 and Department of Pathology,4 College of Physicians and Surgeons, Columbia University, New York, New York 10025; Flow Cytometry Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 100215; and Division of Environmental Health Sciences, Ohio State University, Columbus, Ohio 432106

Received 13 January 2000/Returned for modification 18 February 2000/Accepted 9 May 2000

Helicobacter pylori infection is associated with the development of gastric cancer. In short-term coculture with AGS gastric cells, H. pylori inhibits cell cycle progression and induces dose-dependent apoptosis. Based on the concept that an imbalance between proliferation and apoptosis may contribute to the emergence of gastric cancer, we chronically exposed AGS cells to H. pylori as a model of chronic exposure in humans. The AGS derivatives selected by this process were stably resistant not only to H. pylori-induced apoptosis but also to apoptosis induced by other enteric bacteria and by several toxic agents including radiation and cancer chemotherapy. Like the parental AGS cells, the derivatives underwent G1/S-phase cell cycle inhibition in response to H. pylori. The AGS derivatives displayed a marked decrease in cellular levels of the cell cycle control protein p27kip1. We found a similar decrease in epithelial cell p27kip1 expression in gastric biopsy specimens from H. pylori-infected patients. These findings are consistent with observations that link decreases in the p27kip1 level to increased susceptibility to cancer in mice with p27kip1 deleted and to a poor prognosis of gastric cancer in humans. This is the first demonstration that bacterial infection can lead to apoptosis resistance and to cross-resistance to other inducers of apoptosis such as bacteria, chemotherapeutic agents, and radiation. The development of apoptosis resistance and downmodulation of p27kip1 may contribute to the increased risk for gastric cancer observed in humans chronically exposed to H. pylori.

* Corresponding author. Present address: Division of Gastroenterology, Department of Medicine, Rhode Island Hospital, APC 421, 593 Eddy St., Providence, RI 02818. Phone: (401) 444-5031. Fax: (401) 444-6194. E-mail: smoss1{at}pol.net.

dagger Present address: Department of Gastroenterology, Wolfson Medical Center, Holon 58100, Israel.

Infection and Immunity, September 2000, p. 5321-5328, Vol. 68, No. 9
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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