Chronic Helicobacter pylori Infection Induces an Apoptosis-Resistant Phenotype Associated with Decreased Expression of p27 kip1

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Abstract
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 G 1 /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 p27 kip1 . We found a similar decrease in epithelial cell p27 kip1 expression in gastric biopsy specimens from H. pylori -infected patients. These findings are consistent with observations that link decreases in the p27 kip1 level to increased susceptibility to cancer in mice with p27 kip1 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 p27 kip1 may contribute to the increased risk for gastric cancer observed in humans chronically exposed to H. pylori .