Faculty Collaboration Database

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis. J Clin Invest 2012 Jun;122(6):2092-103

Date

05/09/2012

Pubmed ID

22565310

Pubmed Central ID

PMC3366404

DOI

10.1172/JCI60144

Scopus ID

2-s2.0-84861821128 (requires institutional sign-in at Scopus site)   102 Citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras(G12D), we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras(G12D)-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a Kras(G12D) background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stress-related pathway that is required for oncogenic Kras(G12D)-dependent transformation of the pancreas.

Author List

Hamidi T, Algül H, Cano CE, Sandi MJ, Molejon MI, Riemann M, Calvo EL, Lomberk G, Dagorn JC, Weih F, Urrutia R, Schmid RM, Iovanna JL

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Animals
Apoptosis
Apoptosis Regulatory Proteins
Cell Line, Tumor
Cell Transformation, Neoplastic
DNA-Binding Proteins
Female
Gene Deletion
Gene Expression Regulation, Neoplastic
Humans
Immediate-Early Proteins
Male
Membrane Proteins
Mice
Mice, Mutant Strains
Neoplasm Proteins
Neoplasms, Experimental
Oncogene Protein p21(ras)
Pancreatic Neoplasms
Signal Transduction
Transcription Factor RelB