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

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.

Host microarray analysis reveals a role for the Salmonella response regulator phoP in human macrophage cell death

“…A20 is a zinc-finger protein that regulates cell death and limits inflammation by inhibiting NF-B activity (40). The p27͞Kip1 gene product promotes G 1 cell cycle arrest in certain situations, such as upon Helicobacter pylori infection, that are followed by cell death (41,42). The v-myb gene product is a member of the myb family of proteins, which are transcription factors that affect both cell cycle progression and cell death (43).…”

Gastrin-induced miR-222 promotes gastric tumor development by suppressing p27kip1

“…Patients with H. pylori- induced chronic gastritis also show decreased gastric expression of p27, which is reversed following eradication of the bacterium [54, 55]. Long-term exposure to H. pylori in animal [56] and cell culture [57] models has also been shown to promote an apoptosis-resistant phenotype associated with decreased p27 expression [58]. A very recent paper has also demonstrated reduced p27 expression in gastric carcinoid tumors arising in transgenic mice that was hypergastrinemic as a result of deletion of Men1 and somatostatin along with treatment with omeprazole [59].…”

Helicobacter pylori decreases p27 expression through the delta opioid receptor-mediated inhibition of histone acetylation within the p27 promoter

“…The HS3C cell line is from a single clone that was derived from AGS gastric epithelial cells by continually exposing those AGS cells to increasing concentrations of H. pylori in co-culture [26]. HS3C cells exhibit resistance to apoptosis induced by several diverse stimuli.…”