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lüll PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells Park MA; Yacoub A; Sarkar D; Emdad L; Rahmani M; Spiegel S; Koumenis C; Graf M; Curiel DT; Grant S; Fisher PB; Dent PAutophagy 2008[May]; 4 (4): 513-5Melanoma 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.|*Glioma[MESH]|Adjuvants, Immunologic/metabolism[MESH]|Animals[MESH]|Apoptosis/*physiology[MESH]|Autophagy/*physiology[MESH]|Endoplasmic Reticulum Chaperone BiP[MESH]|Humans[MESH]|Interleukins/genetics/*metabolism[MESH]|Mitogen-Activated Protein Kinases/metabolism[MESH]|Recombinant Fusion Proteins/genetics/*metabolism[MESH]|Signal Transduction/physiology[MESH]|Tumor Cells, Cultured[MESH]|eIF-2 Kinase/genetics/*metabolism[MESH] |