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The pancreatitis-associated protein VMP1, a key regulator of inducible autophagy, promotes Kras(G12D)-mediated pancreatic cancer initiation. Cell Death Dis 2016 07 14;7:e2295 PMID: 27415425 PMCID: PMC4973346

Pubmed ID

27415425

DOI

10.1038/cddis.2016.202

Abstract

Both clinical and experimental evidence have firmly established that chronic pancreatitis, in particular in the context of Kras oncogenic mutations, predisposes to pancreatic ductal adenocarcinoma (PDAC). However, the repertoire of molecular mediators of pancreatitis involved in Kras-mediated initiation of pancreatic carcinogenesis remains to be fully defined. In this study we demonstrate a novel role for vacuole membrane protein 1 (VMP1), a pancreatitis-associated protein critical for inducible autophagy, in the regulation of Kras-induced PDAC initiation. Using a newly developed genetically engineered model, we demonstrate that VMP1 increases the ability of Kras to give rise to preneoplastic lesions, pancreatic intraepithelial neoplasias (PanINs). This promoting effect of VMP1 on PanIN formation is due, at least in part, by an increase in cell proliferation combined with a decrease in apoptosis. Using chloroquine, an inhibitor of autophagy, we show that this drug antagonizes the effect of VMP1 on PanIN formation. Thus, we conclude that VMP1-mediated autophagy cooperate with Kras to promote PDAC initiation. These findings are of significant medical relevance, molecules targeting autophagy are currently being tested along chemotherapeutic agents to treat PDAC and other tumors in human trials.

Author List

Loncle C, Molejon MI, Lac S, Tellechea JI, Lomberk G, Gramatica L, Fernandez Zapico MF, Dusetti N, 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-s2.0-85016946884   9 Citations

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

Animals
Autophagy
Carcinoma, Ductal
Cell Line, Tumor
Cell Proliferation
Cell Survival
Chloroquine
Gene Expression Regulation, Neoplastic
Genes, Reporter
HEK293 Cells
Humans
Luminescent Proteins
Membrane Proteins
Mice
Mice, Transgenic
Pancreas
Pancreatic Neoplasms
Pancreatitis
Pancreatitis-Associated Proteins
Proto-Oncogene Proteins p21(ras)
Signal Transduction
jenkins-FCD Prod-336 69ef4a6b262d135130251597d5d39873903802b5