title: PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298-0035, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Park
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Mohammed
authors.initials: M
authors.lastname: Rahmani
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.forename: Costas
authors.initials: C
authors.lastname: Koumenis
authors.forename: Martin
authors.initials: M
authors.lastname: Graf
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005910:Glioma; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*; D000099180:Interleukin-24
chemical_list: D000276:Adjuvants, Immunologic; D000091342:Endoplasmic Reticulum Chaperone BiP; D007378:Interleukins; D020928:Mitogen-Activated Protein Kinases; D011993:Recombinant Fusion Proteins; D019892:eIF-2 Kinase; D000099180:Interleukin-24; C000717247:HSPA5 protein, human