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

Margaret A. Park, Adly Yacoub, Devanand Sarkar, Luni Emdad, Mohammed Rahmani, Sarah Spiegel, Costas Koumenis, Martin Graf, David T. Curiel, Steven Grant, Paul B. Fisher, Paul Dent

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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.

Original languageBritish English
Pages (from-to)513-515
Number of pages3
JournalAutophagy
Volume4
Issue number4
DOIs
StatePublished - 16 May 2008

Keywords

  • Autophagy
  • Caspase
  • Cell death
  • ER stress

Fingerprint

Dive into the research topics of 'PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells'. Together they form a unique fingerprint.

Cite this