Chronic Helicobacter pylori infection induces an apoptosis-resistant phenotype associated with decreased expression of p27(kip1)

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 contribut e 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 sele cted by this process were stably resistant not only to H. pylori-induced ap optosis but also to apoptosis induced by other enteric bacteria and by seve ral toxic agents including radiation and cancer chemotherapy. Like the pare ntal AGS cells, the derivatives underwent G(1)/S-phase cell cycle inhibitio n 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 s usceptibility to cancer in mice with p27(kip1) deleted and to a poor progno sis of gastric cancer in humans. This is the first demonstration that bacte rial 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 p2 7(kip1) may contribute to the increased risk for gastric cancer observed in humans chronically exposed to H. pylori.