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

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

Margaret A Park  1 , Adly Yacoub, Devanand Sarkar, Luni Emdad, Mohammed Rahmani, Sarah Spiegel, Costas Koumenis, Martin Graf, David T Curiel, Steven Grant, Paul B Fisher, Paul Dent
Affiliations

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

Margaret A Park et al. Autophagy. 2008 May.

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.

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Figures

Figure 1
Figure 1
GST-MDA-7 causes PERK-dependent vacuolization and JNK pathway activation in transformed cells that leads to cell death. Exposure to GST-MDA-7 causes a PERK-dependent activation of the JNK pathway and a PERK-dependent inactivation of the ERK1/2 pathway. Enhanced JNK pathway signaling plays a key role in the activation of pro-caspase 2, pro-caspase 4 and cathepsin B. Activation of cathepsin B promotes the cleavage/activation of the BH3 domain protein BID. Elevated JNK pathway signaling also activates BAX. Inactivation of the ERK1/2 pathway facilitates activation of BAD and BIM. Thus GST-MDA-7, via PERK signaling, promotes increased activity of at least 4 BH3 domain proteins which all act to cause mitochondrial dysfunction and ultimately promote cell killing.
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