PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells

Autophagy. 2008 May;4(4):513-5. doi: 10.4161/auto.5725. Epub 2008 Feb 13.

Abstract

Melanoma differentiation associated gene-7/interleukin 24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The studies by Yacoub et al. (Mol Cancer Ther 2008; 7:314-29) further defines the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that were dependent on activation of JNK1-3 with subsequent activation of BAX and the induction of mitochondrial dysfunction. Activation of JNK1-3 was dependent upon protein kinase R-like endoplasmic reticulum kinase (PERK) and GST-MDA-7 lethality was suppressed in PERK(-/-) cells. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methyladenine, expression of HSP70 or of BiP/GRP78, or by knockdown of ATG5 or Beclin 1 expression, but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin 1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data demonstrate that GST-MDA-7 induces an ER stress response that, via the induction of autophagy, is causal in the activation of pro-apoptotic pathways that converge on the mitochondrion and ultimately culminate in decreased glioma cell survival.

Publication types

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

MeSH terms

  • Adjuvants, Immunologic / metabolism
  • Animals
  • Apoptosis / physiology*
  • Autophagy / physiology*
  • Glioma*
  • Humans
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • Signal Transduction / physiology
  • Tumor Cells, Cultured
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism*

Substances

  • Adjuvants, Immunologic
  • Interleukins
  • Recombinant Fusion Proteins
  • interleukin-24
  • PERK kinase
  • eIF-2 Kinase
  • Mitogen-Activated Protein Kinases