Suppression of autophagy impedes glioblastoma development and induces senescence

Autophagy. 2016 Sep;12(9):1431-9. doi: 10.1080/15548627.2016.1190053. Epub 2016 Jun 15.


The function of macroautophagy/autophagy during tumor initiation or in established tumors can be highly distinct and context-dependent. To investigate the role of autophagy in gliomagenesis, we utilized a KRAS-driven glioblastoma mouse model in which autophagy is specifically disrupted via RNAi against Atg7, Atg13 or Ulk1. Inhibition of autophagy strongly reduced glioblastoma development, demonstrating its critical role in promoting tumor formation. Further supporting this finding is the observation that tumors originating from Atg7-shRNA injections escaped the knockdown effect and thereby still underwent functional autophagy. In vitro, autophagy inhibition suppressed the capacity of KRAS-expressing glial cells to form oncogenic colonies or to survive low serum conditions. Molecular analyses revealed that autophagy-inhibited glial cells were unable to maintain active growth signaling under growth-restrictive conditions and were prone to undergo senescence. Overall, these results demonstrate that autophagy is crucial for glioma initiation and growth, and is a promising therapeutic target for glioblastoma treatment.

Keywords: ATG7; RCAS; autophagy; brain; cancer; glioblastoma; metabolism; senescence; tumor.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy*
  • Autophagy-Related Protein 7 / genetics*
  • Autophagy-Related Protein 7 / metabolism
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cellular Senescence
  • Chickens
  • Fibroblasts / metabolism
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Hypoxia
  • Mice
  • Neuroglia / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Signal Transduction


  • ATG13 protein, mouse
  • Apoptosis Regulatory Proteins
  • Atg7 protein, mouse
  • RNA, Small Interfering
  • Autophagy-Related Protein-1 Homolog
  • Ulk1 protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Autophagy-Related Protein 7