Abstract 59: Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer

Helicobacter pylori (H.pylori) infection of the gastric mucosa is strongly associated with chronic gastritis, peptic ulcer disease and gastric cancer. Individuals infected with H.pylori possessing CagA protein produce more reactive oxygen species (ROS) and increase the risk of developing gastric cancer. Sirtuins are NAD+ dependent deacetylases that regulate cellular metabolism in response to stress. Recently, mitochondrial sirtuin, SIRT3, is known to be a tumor suppressor via its ability to suppress ROS and regulate hypoxia inducible factor 1α (HIF-1α). However, it has not been investigated whether increased ROS production by H.pylori is regulated by SIRT3 via HIF-1α regulation and is mediated through intracellular CagA. We aimed to investigate the correlation between SIRT3, ROS and HIF-1α in H.pylori infected gastric epithelial cells. In this study, we showed that SIRT3 deficient AGS cells exhibited augmented HIF-1α protein stabilization and transcriptional activity in hypoxic condition. We also found that H.pylori CagA downregulated SIRT3 activity and induced ROS production through HIF-1α stabilization, similar to hypoxic condition in gastric epithelial cells. Overexpression of SIRT3 inhibited the stabilization of HIF-1α protein and attenuated the increase in HIF-1α transcriptional activity in hypoxia. Moreover, H.pylori CagA attenuated HIF-1α stability and transcriptional activity in SIRT3 overexpressed gastric epithelial cells. Taken together, these findings provide a valuable insight into the potential role of SIRT3 in the development of gastric cancer by regulating the HIF-1α protein. Citation Format: doyeon lee, SungSook Yu, Dawoon E.Jung1 Jung, YeoSong Lee, Beom Ku Choi, Yong Chan Lee. Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 59.