Polyamine Dysregulation in the Gastric Epithelium during Helicobacter pylori Infection and its Impact on Gastric Carcinogenesis
NIH
VANDERBILT UNIVERSITY
PROJECT SUMMARY Helicobacter pylori colonizes the stomach of about 50% of the world’s population and is the strongest known risk factor for developing gastric cancer, the fourth most common cause of cancer related deaths. Failure of the host response to control the infection leads to persistent inflammation, which initiates disease progression from chronic gastritis through a histological “Correa Cascade” that results in gastric carcinoma in 1-3% of all those infected. Due to antibiotic resistance, and the fact that antibiotic treatment may not be effective in reducing cancer risk once precancerous lesions are present, we need to develop new therapeutic strategies to limit progression to dysplasia and carcinoma. Our lab investigates the role of the polyamines, putrescine, spermidine, and spermine in gastric inflammation and carcinogenesis. Putrescine is sequentially converted to spermidine and spermine, which is back-converted to spermidine by spermine oxidase (SMOX). We have shown that SMOX expression is elevated in human and mouse gastric tissues infected with H. pylori. Furthermore, infected C57BL/6 Smox–/– mice exhibit depleted spermidine levels, and a decrease in gastritis and carcinogenic signaling compared to wild-type mice. Using FVB/N INS-GAS mice prone to developing gastric dysplasia and intramucosal carcinoma with H. pylori infection, we have seen that Smox–/– mice infected with H. pylori exhibit a significant reduction in gastric intramucosal carcinoma and extent of dysplasia. Spermine catabolism by SMOX generates 3-aminopropanol, which can spontaneously form acrolein, a reactive electrophilic aldehyde that has the potential to damage DNA and proteins. Our preliminary findings demonstrate that acrolein is produced in gastric tissues of H. pylori-infected FVB/N INS-GAS mice and is significantly reduced in Smox–/– FVB/N INS-GAS mice. Additionally, spermidine is an essential substrate for the synthesis of hypusine, a unique amino acid that is only found in the protein eukaryotic translation initiation factor 5A (EIF5A) by the action of the enzyme deoxyhypusine synthase (DHPS). Our recent work with human gastric organoids has revealed induction of hypusinated EIF5A levels with H. pylori infection, which was ablated with the chemical inhibitor of the pathway. Proteomic analysis on these organoids implicated hypusination as a critical pathway for oncogenesis. Taken together, we hypothesize that polyamine dysregulation due to SMOX activity in H. pylori-infected gastric epithelial cells leads to the generation of spermidine and acrolein, and upregulation of the hypusination pathway resulting in increased risk for gastric cancer development. Our specific aims are to determine: 1) the role of SMOX activity in gastric carcinogenesis, including effects of spermidine, spermine and acrolein in FVB/N INS-GAS mice. 2) if spermidine generated by SMOX contributes to gastric cancer development through hypusination using studies in human gastric organoids and mice with an epithelial-specific deletion of Dhps. This proposal seeks to elucidate the mechanisms by which SMOX induces gastric disease progression, thus identifying novel pathways to be targeted for therapeutic benefit, while providing the ideal training for my future career as a principal investigator. PROJECT NARRATIVE Helicobacter pylori infects half of the world’s population and is the strongest known risk factor for gastric cancer; however, traditional treatment with antibiotics is often ineffective, especially once precancerous lesions are present. We have previously shown that polyamines are involved in gastric inflammation and carcinogenesis, and our data indicate that the enzyme spermidine oxidase (SMOX) regulates key pathways involved in the progression to cancer. This project will investigate the mechanisms by which SMOX contributes to gastric carcinogenesis by examining its metabolic products, spermidine and the toxic metabolite acrolein, and the enhancement of a pathway involved in translation, hypusination, all of which could contribute to carcinogenetic signaling, with the ultimate goal of discovering novel pathways to be therapeutically targeted.
Training, Individual