Abstract
Peroxiredoxin-1 (Prdx1), a member of the thioredoxin (Txn) system, is overexpressed and correlates with poor prognosis in pancreatic cancer patients and can suppress Kras signaling through redox-mediated inhibition of ERK and AKT in lung and breast cancer. Its redox function is maintained by Txn and sulfiredoxin (Srxn), and its tumor promoting functions are activated by post-translational modification. We studied the role of the Txn system in pancreatic neoplasia and cancer by determining how it regulates the phosphorylation of Kras effectors and by determining its association with patient survival. We found that elevated Prdx1 nuclear localization significantly correlated with better patient survival. Our data also demonstrate that the expression of the Txn system is dysregulated, with elevated Prdx1 expression and significantly decreased Txn and Srxn expression in pancreatic lesions of targeted mutant Kras mouse models. This correlated with distinct differences in the interconversion of Prdx1 oligomers that affect its ability to regulate ERK and AKT phosphorylation. Our data also suggest that Prdx1 post-translational modification and oligomerization suppress Prdx1 mediated redox regulation of ERK phosphorylation. We observed distinct differences in Txn expression and in the ability of pTyr-Prdx1 to bind to pERK in a PanIN model of pancreatic neoplasia as compared to an IPMN model, indicating a distinct difference in the function of post-translationally modified Prdx1 in cells with less Txn expression. Modified Txn system function and post-translational regulation may therefore play a significant role in pancreatic tumorigenesis by altering Kras effector phosphorylation and inhibiting the tumor suppressive redox functions of Prdx1.
Highlights
Improvement of pancreatic cancer therapy requires sensitive early detection techniques and a better understanding of the biology of pancreatic neoplasia
We studied the role of the Txn system in pancreatic neoplasia and cancer by determining how it regulates the phosphorylation of Kras effectors and by determining its association with patient survival
We demonstrate that distinct differences in the ability of Prdx1 to regulate ERK and AKT phosphorylation are associated with changes in Prdx1 post-translational modification, oligomerization, and interaction with ERK
Summary
Improvement of pancreatic cancer therapy requires sensitive early detection techniques and a better understanding of the biology of pancreatic neoplasia. Dysregulation of Nrf and the Txn system (through post-translational modification) can have significant effects on tumorigenesis and the response to therapy by modifying the ability of these antioxidant proteins to affect transcription, nuclear chaperoning, and the response of cancer cells to oxidative stress associated with chemotherapy and radiation [10,11,12]. Overoxidation, phosphorylation, and oligomerization of Prdx significantly modifies its cofactor and peroxidase functions [15, 16], which will significantly alter its ability to regulate the activity of redox sensitive transcription factors and signaling proteins. We characterized changes in the expression and function of the Txn system during pancreatic neoplasia and cancer and investigated its role in regulating mutant Kras associated pancreatic tumorigenesis
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