Abstract A16: 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 tumorigenesis. Nrf2 regulates a battery of antioxidant genes, including peroxiredoxin-1 (Prdx-1), that 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. We are therefore investigating the role of Prdx-1 and its oxidation states in oncogenic signaling pathways in mutant Kras models of pancreatic tumorigenesis and neoplasia. Our data demonstrate that Prdx1 is localized to the nucleus in normal c57-BL6 mice and exclusively located in the cytoplasm in normal pancreatic cells in the EL-Kras model of pancreatic neoplasia. Moreover, in acinar to ductal metaplatic pancreatic cells in EL-Kras mice, there is an increase in cytoplasmic Prdx1 expression and evidence of nuclear staining. Papillary cells in lesions of EL-Kras mice have apical Prdx-1 expression and ductal cells lining these lesions have higher cytoplasmic Prdx-1 expression and some nuclear Prdx-1 localization. This suggests that throughout tumor progression, Prdx-1 is differentially regulated. In vitro, neoplastic and tumorigenic pancreatic cell lines have more total Prdx-1 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 fatty acids that control pancreatic neoplasia. In addition, ERK phosphorylation was also modified by fatty acid treatment in wildtype and mutant Kras normal, neoplastic, and tumorigenic cell lines. Our data therefore suggests 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 A. Schultz, Rital Shah, Brian DeCant, David Bentrem, Paul Grippo. Mutant Kras associated protein oxidation in pancreatic neoplasia. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A16.