title: Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells.
abstract: Sustained expression of CagA, the type IV secretion effector of Helicobacter pylori, is closely associated with the development of gastric cancer. However, we observed that after translocation, CagA is degraded by autophagy and therefore short lived. Autophagy and CagA degradation are induced by the H. pylori vacuolating cytotoxin, VacA, which acted via decreasing intracellular glutathione (GSH) levels, causing reactive oxygen species (ROS) accumulation and Akt activation. Investigating this further, we found that CagA specifically accumulated in gastric cells expressing CD44, a cell-surface marker associated with cancer stem cells. The autophagic pathway in CD44-positive gastric cancer stem-like cells is suppressed because of their resistance to ROS, which is supported by increased intracellular GSH levels. These findings provide a molecular link between H. pylori and gastric carcinogenesis through the specific accumulation of CagA in gastric cancer stem-like cells.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsugawa
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
authors.forename: Toshiya
authors.initials: T
authors.lastname: Hirayama
authors.forename: Kenro
authors.initials: K
authors.lastname: Hirata
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.forename: Juntaro
authors.initials: J
authors.lastname: Matsuzaki
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism*; D001343:Autophagy; D001426:Bacterial Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism / Q000382:microbiology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000276:immunology*; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D017382:Reactive Oxygen Species; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori