The Helicobacter pylori's protein VacA has direct effects on the regulation of cell cycle and apoptosis in gastric epithelial cells

Abstract

In this study, we have evaluated the effects on cell cycle regulation of VacA alone and in combination with other two Helicobacter pylori proteins, cytotoxin-associated protein (CagA) and HspB, using the human gastric epithelial cells (AGS). Our results indicate that VacA alone was able to inhibit the G1 to S progression of the cell cycle. The VacA capacity of inhibiting cell progression from G1 to S phase was also observed when cells were co-transfected with CagA or HspB. Moreover, VacA over-expression caused apoptosis in AGS cells through activation of caspase 8 and even more of caspase 9, thus indicating an involvement of both the receptor-mediated and the mitochondrial pathways of apoptosis. Indeed, the two pathways probably can co-operate to execute cell death with a prevalence of the mitochondrial pathways. Our data taken together provide additional information to further enhance our understanding of the molecular mechanism by which H. pylori proteins alter the growth status of human gastric epithelial cells.

Helicobacterpylori-induced modification of the histone H3 phosphorylation status in gastric epithelial cells reflects its impact on cell cycle regulation

“…18,29 Others demonstrated that VacA alone was able to inhibit the G 1 to S progression in gastric epithelial cells. 30 Thus, we conclude that a G 1 /S delay contributed little, or not at all, to the decrease of pH3Ser10.…”

Role of Connexin 43 in Helicobacter pylori VacA-Induced Cell Death

“…Effects of VacA on mitochondria include reduction in mitochondrial transmembrane potential, cytochrome c release, and mitochondrial network fragmentation (30,(38)(39)(40)(41)(42)(43), which can lead to poly(ADPribose) polymerase (PARP) cleavage, reduction of cellular ATP content, and impaired cell cycle progression (9,35,(41)(42)(43). The proapoptotic factors BAX and BAK, as well as dynamin-related protein 1 (Drp1), have roles in VacA-mediated cell death (31, 42,44).…”

“…The proapoptotic factors BAX and BAK, as well as dynamin-related protein 1 (Drp1), have roles in VacA-mediated cell death (31, 42,44). VacA can cause cell death in several cell lines, including HeLa (30, 38, 39,45), AGS (20,36,37,41,46), and AZ-521 cells (25,35,42,44,47), but among these cell types, AZ-521 cells are the most susceptible to VacA-mediated killing (35). The molecular mechanisms underlying this enhanced susceptibility of AZ-521 cells are not understood.…”

Epidemiological Link between Gastric Disease and Polymorphisms in VacA and CagA

“…VacA is another important toxin that is produced and secreted by all H. pylori strains (4,11) and was previously shown to have various modes of action (12,16,27,39,49,50,52,56). Like CagA, VacA has been shown to contain a number of polymorphisms.…”