Abstract 2132: Mutant Kras associated protein oxidation in pancreatic neoplasia

Abstract

Abstract Recent studies have suggested that mutant Kras associated activation of the Nrf2 pathway may have a significant role in pancreatic cancer (PaCa) tumorigenesis. Nrf2 regulates a battery of antioxidant genes, including peroxiredoxin-1 (Prdx-1), thioredoxin (Txn), and sulfiredoxin (Srxn), which are responsible for maintaining redox homeostasis in the cell. While ROS detoxification may have significant roles in cancer, several non-classical mechanisms of redox signaling associated with protein oxidation and phosphorylation are also important in tumorigenesis. Prdx-1 can regulate transcription as a cofactor in multiple oxidation states, represses tumorigenesis in its reduced state, and can act as a nuclear chaperone in elevated states of oxidation and when phosphorylated. Txn and Srxn prevent Prdx-1 overoxidation. We are therefore investigating the role of Prdx-1 oxidation and Txn and Srxn regulation in oncogenic signaling pathways in mutant Kras models of pancreatic tumorigenesis and neoplasia. Our data suggest that throughout tumor progression, Prdx-1 expression and localization are differentially regulated. These changes also correlated with reduced Txn and Srxn expression in lesions. In vitro, neoplastic and tumorigenic pancreatic cell lines have more total prdx-1 expression and oxidized Prdx-1 expression than non-tumorigenic cell lines. Moreover, cells that have mutant Kras were associated with higher levels of protein oxidation than those with wildtype Kras expression. Interestingly, mutant Kras was also associated with differences in pERK interaction with Prdx-1, which was also differentially regulated by NOX inhibitors and omega-3 fatty acids that control pancreatic neoplasia. ERK inhibitors also differentially affected Prdx1 expression in pancreatic cells in vitro. In addition, AKT, ERK, and FOXO3a phosphorylation were also modified by DPI treatment (NOX inhibitor) and omega-3 fatty acid treatment in wildtype and mutant Kras normal, neoplastic, and tumorigenic cell lines. We therefore conclude that mutant Kras is associated with elevated levels of Prdx-1 oxidation and that Kras-mediated activation of ERK could be associated with changes in Prdx-1 signaling in pancreatic neoplasia. Citation Format: Michelle Schultz, Brian DeCant, Andrew Diaz, Sharon Solman, Rital Shah, David Bentrem, Paul J. Grippo. Mutant Kras associated protein oxidation in pancreatic neoplasia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2132. doi:10.1158/1538-7445.AM2015-2132