The discovery that H. pylori is an important factor in the development of peptic ulcers has dramatically changed the way ulcer patients are treated. Ulcers heal faster in persons treated with antibiotics in addition to acid medication. One possible explanation for this observation is that cell generation is impaired by H. pylori; thus, ulcer healing occurs more rapidly in the absence of H. pylori infection. Epidemiological studies have strongly associated H. pylori with gastric carcinogenesis. These data led the World Health Organization to designate H. pylori a Class I carcinogen. It is felt that at least half of all gastric cancers are attributed to infection with this bacterium. However, there is little known as to how H. pylori may directly effect gastric cells to cause gastric cancer. Epidemiological data supports this bacterium as a cofactor because it causes chronic gastritis which may progress to atrophic gastritis, a precursor lesion for intestinal type gastric cancer. However, this bacterium is also strongly linked to diffuse gastric cancer which occurs in otherwise normal (non-atrophic) gastric mucosa, where the bacterial infection is present at the time the cancer occurs. In vivo studies show that some bacterial strains cause significant cell injury in the absence of a rise in gastric apoptosis. One explanation is that the bacterium, while causing cell injury, is able to down regulate apoptosis. The decrease in apoptosis in injured gastric cells is one possible mechanism by which this bacterium might directly increase the susceptibility of gastric cells to carcinogenic conversion. This grant proposes to evaluate the direct effects of H. pylori on the cell death in gastric epithelial cells.
The Specific Aims of this project are: 1)To better elucidate the involvement of the p53 pathway in H. pylori induced apoptosis by determining the extent of phosphorylation of p53 in cells exposed to H. pylori strains and the importance of phosphorylation at serine-15,-20 and-46 in regard to apoptosis. Also, to evaluate p53 phosphorylation in response to ROS species in the absence of H. pylori and in the presence of H. pylori and antioxidants. 2)To determine the involvement and significance of activation of p53AIPl, which is activated by phosphorylating p53 at serine-46. The mechnism of bacterial exposure on the gastric epithelial cell death has not been studied in regard to p53. These studies are important to elucidate specific p53 pathways that are modulated by exposure to this bacterium, resulting in an regulating cell death. Specifically, whether or not stimulation of reactive oxygen species (ROS) by H. pylori is essential for p53 phosphorylation leading to apoptosis. These studies will help to establish how bacteria can increase apoptosis possibly through generation of ROS and in specific circumstances this may alter one's risk of developing cancer.
| Ashktorab, Hassan; Dashwood, Rod H; Dashwood, Mohaiza M et al. (2008) H. pylori-induced apoptosis in human gastric cancer cells mediated via the release of apoptosis-inducing factor from mitochondria. Helicobacter 13:506-17 |
| Ashktorab, Hassan; Daremipouran, Mohammad; Wilson, Melissa et al. (2007) Transactivation of the EGFR by AP-1 is induced by Helicobacter pylori in gastric cancer. Am J Gastroenterol 102:2135-46 |
| Ashktorab, H; Frank, S; Khaled, A R et al. (2004) Bax translocation and mitochondrial fragmentation induced by Helicobacter pylori. Gut 53:805-13 |
| Ashktorab, Hassan; Neapolitano, Mattew; Bomma, Chandara et al. (2002) In vivo and in vitro activation of caspase-8 and -3 associated with Helicobacter pylori infection. Microbes Infect 4:713-22 |
