A dual role for autophagy in a murine model of lung cancer

Nat Commun. 2014;5:3056. doi: 10.1038/ncomms4056.

Abstract

Autophagy is a mechanism by which starving cells can control their energy requirements and metabolic states, thus facilitating the survival of cells in stressful environments, in particular in the pathogenesis of cancer. Here we report that tissue-specific inactivation of Atg5, essential for the formation of autophagosomes, markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage of tumour-bearing mice. Autophagy-defective lung cancers exhibit impaired mitochondrial energy homoeostasis, oxidative stress and a constitutively active DNA damage response. Genetic deletion of the tumour suppressor p53 reinstates cancer progression of autophagy-deficient tumours. Although there is improved survival, the onset of Atg5-mutant KRas(G12D)-driven lung tumours is markedly accelerated. Mechanistically, increased oncogenesis maps to regulatory T cells. These results demonstrate that, in KRas(G12D)-driven lung cancer, Atg5-regulated autophagy accelerates tumour progression; however, autophagy also represses early oncogenesis, suggesting a link between deregulated autophagy and regulatory T cell controlled anticancer immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Protein 5
  • Disease Models, Animal*
  • Disease Progression
  • Female
  • Gene Deletion
  • Gene Expression Profiling
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / physiopathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / physiology*
  • Mutation / genetics
  • T-Lymphocytes, Regulatory / pathology
  • T-Lymphocytes, Regulatory / physiology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Microtubule-Associated Proteins
  • Tumor Suppressor Protein p53