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Genetic inactivation of the pancreatitis-inducible gene Nupr1 impairs PanIN formation by modulating Kras(G12D)-induced senescence. Cell Death Differ 2014 Oct;21(10):1633-41 PMID: 24902898 PMCID: PMC4158688

Pubmed ID

24902898

DOI

10.1038/cdd.2014.74

Abstract

Nuclear protein 1 (Nupr1), a small chromatin protein, has a critical role in cancer development, progression and resistance to therapy. Previously, we had demonstrated that Nupr1 cooperates with Kras(G12D) to induce pancreas intraepithelial neoplasias (PanIN) formation and pancreatic ductal adenocarcinoma development in mice. However, the molecular mechanisms by which Nupr1 influences Kras-mediated preneoplastic growth remain to be fully characterized. In the current study, we report evidence supporting a role for Nupr1 as a gene modifier of Kras(G12D)-induced senescence, which must be overcome to promote PanIN formation. We found that genetic inactivation of Nupr1 in mice impairs Kras-induced PanIN, leading to an increase in β-galactosidase-positive cells and an upregulation of surrogate marker genes for senescence. More importantly, both of these cellular and molecular changes are recapitulated by the results of mechanistic experiments using RNAi-based inactivation of Nupr1 in human pancreatic cancer cell models. In addition, the senescent phenotype, which results from Nupr1 inactivation, is accompanied by activation of the FoxO3a-Skp2-p27(Kip1)-pRb-E2F pathway in vivo and in vitro. Thus, combined, these results show, for the first time, that Nupr1 aids oncogenic Kras to bypass senescence in a manner that cooperatively promotes PanIN formation. Besides its mechanistic importance, this new knowledge bears medical relevance as it delineates early pathobiological events that may be targeted in the future as a means to interfere with the formation of preneoplastic lesions early during pancreatic carcinogenesis.

Author List

Grasso D, Garcia MN, Hamidi T, Cano C, Calvo E, Lomberk G, Urrutia R, Iovanna JL

Authors

Gwen Lomberk PhD Associate 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




Scopus

2-s2.0-84939779108   15 Citations

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

Animals
Carcinoma, Pancreatic Ductal
Cell Line
Cell Transformation, Neoplastic
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p27
DNA-Binding Proteins
Forkhead Box Protein O3
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Knockout
Neoplasm Proteins
Pancreatic Neoplasms
Proto-Oncogene Proteins p21(ras)
RNA Interference
RNA, Small Interfering
S-Phase Kinase-Associated Proteins
Up-Regulation
beta-Galactosidase
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad