Thioredoxin system-mediated regulation of mutant Kras associated pancreatic neoplasia and cancer
| Autor: | Windel E. Mascarinas, Andrew M. Diaz, Ronald D McKinney, Anna R. Lay, Yinglin Xia, Paul J. Grippo, David W. Dawson, Sharon Smite, Brian DeCant, Carola A. Neumann, David J. Bentrem, Michelle A. Schultz |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway pancreatic cancer medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Pancreatic cancer Medicine Protein kinase B business.industry Cancer medicine.disease 3. Good health 030104 developmental biology Oncology 030220 oncology & carcinogenesis Immunology thioredoxin (Txn) system Cancer research Kras Phosphorylation KRAS Thioredoxin business Carcinogenesis peroxiredoxin-1 (Prdx1) Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Michelle A. Schultz 1, 2 , Andrew M. Diaz 1 , Sharon Smite 1 , Anna R. Lay 3 , Brian DeCant 1 , Ronald McKinney 1 , Windel E. Mascarinas 2 , Yinglin Xia 1 , Carola Neumann 4 , David Bentrem 2 , David W. Dawson 3 and Paul J. Grippo 1, 2 1 Division of Gastroenterology, Department of Medicine, University of Illinois-Chicago, Chicago IL 60612, USA 2 Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA 3 Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA 4 Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center, Pittsburgh PA 15232, USA Correspondence to: Michelle A. Schultz, email: buffalosoldierms@gmail.com , maschult@uic.edu Keywords: peroxiredoxin-1 (Prdx1), thioredoxin (Txn) system, Kras, pancreatic cancer Received: July 13, 2016 Accepted: June 26, 2017 Published: October 04, 2017 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. |
| Databáze: | OpenAIRE |
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