Dual regulation by apurinic/apyrimidinic endonuclease-1 inhibits gastric epithelial cell apoptosis during Helicobacter pylori infection.

Human apurinic/apyrimidinic endonuclease-1 (APE-1), a key enzyme involved in repair of oxidative DNA base damage, is an important transcriptional coregulator. We previously reported that Helicobacter pylori infection induces apoptosis and increases APE-1 expression in human gastric epithelial cells (GEC). Although both the DNA repair activity and the acetylation-mediated transcriptional regulation of APE-1 are required to prevent cell death, the mechanisms of APE-1-mediated inhibition of infection-induced apoptosis are unclear. Here, we show that short hairpin RNA-mediated stable suppression of APE-1 results in increased apoptosis in GEC after H. pylori infection. We show that programmed cell death involves both the caspase-9-mediated mitochondrial pathway and the caspase-8-dependent extrinsic pathway by measuring different markers for both the pathways. Overexpression of wild-type APE-1 in APE-1-suppressed GEC reduced apoptosis after infection; however, overexpression of the DNA repair mutant or the nonacetylable mutant of APE-1 alone was unable to reduce apoptosis, suggesting that both DNA repair and acetylation functions of APE-1 modulate programmed cell death. We show for the first time that the DNA repair activity of APE-1 inhibits the mitochondrial pathway, whereas the acetylation function inhibits the extrinsic pathway during H. pylori infection. Thus, our findings establish that the two different functions of APE-1 differentially regulate the intrinsic and the extrinsic pathway of H. pylori-mediated GEC apoptosis. As proapoptotic and antiapoptotic mechanisms determine the development and progression of gastritis, gastric ulceration, and gastric cancer, this dual regulatory role of APE-1 represents one of the important molecular strategies by H. pylori to sustain chronic infection.