Dual Regulation by Apurinic/Apyrimidinic Endonuclease-1 Inhibits Gastric Epithelial Cell Apoptosis during Helicobacter pylori Infection

Abstract

Abstract 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. Cancer Res; 70(7); 2799–808