Autophagy suppresses tumorigenesis through elimination of p62

Cell. 2009 Jun 12;137(6):1062-75. doi: 10.1016/j.cell.2009.03.048.

Abstract

Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulated p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-kappaB regulation and gene expression and to promote tumorigenesis. Thus, defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aneuploidy
  • Animals
  • Apoptosis
  • Autophagy*
  • Cell Line
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Mice
  • Mitochondria / metabolism
  • Molecular Chaperones / metabolism
  • NF-kappa B / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Oxidative Stress
  • Protein Disulfide-Isomerases / metabolism
  • Sequestosome-1 Protein
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Gtf2h1 protein, mouse
  • Molecular Chaperones
  • NF-kappa B
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Transcription Factors
  • Protein Disulfide-Isomerases

Associated data

  • GEO/GSE15182