Autophagy Promotes Tumor Cell Survival and Restricts Necrosis, Inflammation, and Tumorigenesis

Cancer Cell. 2006 Jul;10(1):51-64. doi: 10.1016/j.ccr.2006.06.001.

Abstract

Defective apoptosis renders immortalized epithelial cells highly tumorigenic, but how this is impacted by other common tumor mutations is not known. In apoptosis-defective cells, inhibition of autophagy by AKT activation or by allelic disruption of beclin1 confers sensitivity to metabolic stress by inhibiting an autophagy-dependent survival pathway. While autophagy acts to buffer metabolic stress, the combined impairment of apoptosis and autophagy promotes necrotic cell death in vitro and in vivo. Thus, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors, but this necrosis is associated with inflammation and accelerated tumor growth. Thus, autophagy may function in tumor suppression by mitigating metabolic stress and, in concert with apoptosis, by preventing death by necrosis.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / physiology*
  • Beclin-1
  • Cell Line, Transformed
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Cell Transformation, Neoplastic / genetics
  • Disease Progression
  • HeLa Cells
  • Humans
  • Inflammation / genetics
  • Inflammation / pathology*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Microscopy, Electron, Transmission
  • Models, Biological
  • NF-kappa B p50 Subunit / metabolism
  • Necrosis
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Neoplasms / ultrastructure
  • Proteins / genetics
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Transfection

Substances

  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • NF-kappa B p50 Subunit
  • Proteins
  • Proto-Oncogene Proteins c-akt