Helicobacter pylori CagA protein activates Akt and attenuates chemotherapeutics-induced apoptosis in gastric cancer cells
Journal
Oncotarget
Journal Volume
8
Journal Issue
69
Pages
113460-113471
Date Issued
2017
Author(s)
Abstract
Infection with cagA-positive Helicobacter pylori is associated with a higher risk of gastric cancer. The cagA gene product, CagA, is translocated into gastric epithelial cells and perturbs host cellular biological functions. Etoposide, a topoisomerase II inhibitor widely used to couple DNA damage to apoptosis, is a common cytotoxic agent used for advanced gastric cancer. We investigate the effect of CagA on etoposideinduced apoptosis in gastric cancer cells to elucidate whether CagA play a role in gastric carcinogenesis via impairing DNA damage-dependent apoptosis. AGS cell lines stably expressing CagA isolated from H. pylori 26695 strain were established. In the presence of etoposide, viability of parental AGS cells was decreased in a time-and dose-dependent manner, whereas CagA-expressing AGS cells were less susceptible to etoposide induced cell-killing effect. Suppression of etoposide-induced apoptosis was shown in CagA-expressing but not in parental AGS cells by DNA fragmentation, cell cycle, and annexin-V assays. This inhibitory effect of etoposide-induced apoptosis conferred by CagA was also demonstrated in SCM1 and MKN45 gastric cancer cell lines, with two additional chemotherapeutics, 5-FU and cisplatin. The effect of Akt activation on inhibition of etoposide-induced cytotoxicity by CagA was also evaluated. CagA expression and etoposide administration activate Akt in a dose-dependent manner. Enhancement of etoposide cytotoxicity by a PI-3-kinase inhibitor, LY294002, was evident in parental but was attenuated in CagA-expressing AGS cells. CagA may activate Akt, either in the absence or presence of etoposide, potentially contributing to gastric carcinogenesis associated with H. pylori infection and therapeutic resistance by impairing DNA damage-dependent apoptosis. ? Lan et al.
Subjects
Akt; CagA; Chemotherapeutics; Helicobacter pylori
SDGs
Other Subjects
2 morpholino 8 phenylchromone; CagA protein; cisplatin; DNA; etoposide; fluorouracil; lipocortin 5; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein kinase B; AGS cell line; antineoplastic activity; apoptosis; Article; bacterial strain; cancer chemotherapy; cancer resistance; cell cycle assay; cell killing; cell specificity; cell viability; concentration response; controlled study; DNA damage; DNA degradation; DNA fragmentation; drug cytotoxicity; drug potentiation; enzyme activation; genetic transfection; Helicobacter infection; Helicobacter pylori; human; human cell; IC50; MKN45 cell line; nonhuman; protein analysis; protein expression; protein function; SC-M1 cell line; stomach cancer; stomach carcinogenesis
Publisher
Impact Journals LLC
Type
journal article