Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas. Academic Article uri icon

Overview

abstract

  • Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed KrasG12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals.

publication date

  • November 16, 2017

Research

keywords

  • Adenocarcinoma in Situ
  • Carcinoma, Pancreatic Ductal
  • NF-E2-Related Factor 2
  • Pancreatic Neoplasms
  • Proto-Oncogene Proteins c-mdm2

Identity

PubMed Central ID

  • PMC5730340

Scopus Document Identifier

  • 85034422866

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2017.10.011

PubMed ID

  • 29153842

Additional Document Info

volume

  • 32

issue

  • 6