Thioredoxin system-mediated regulation of mutant Kras associated pancreatic neoplasia and cancer

Michelle A. Schultz*, Andrew M. Diaz, Sharon Smite, Anna R. Lay, Brian DeCant, Ronald McKinney, Windel E. Mascarinas, Yinglin Xia, Carola Neumann, David Bentrem, David W. Dawson, Paul J. Grippo

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)92667-92681
Number of pages15
JournalOncotarget
Volume8
Issue number54
DOIs
StatePublished - Jan 1 2017

Keywords

  • Kras
  • Pancreatic cancer
  • Peroxiredoxin-1 (Prdx1)
  • Thioredoxin (Txn) system

ASJC Scopus subject areas

  • Oncology

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    Schultz, M. A., Diaz, A. M., Smite, S., Lay, A. R., DeCant, B., McKinney, R., Mascarinas, W. E., Xia, Y., Neumann, C., Bentrem, D., Dawson, D. W., & Grippo, P. J. (2017). Thioredoxin system-mediated regulation of mutant Kras associated pancreatic neoplasia and cancer. Oncotarget, 8(54), 92667-92681. https://doi.org/10.18632/oncotarget.21539