PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells.
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.
Park
Margaret A
MA
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298-0035, USA.
Yacoub
Adly
A
Sarkar
Devanand
D
Emdad
Luni
L
Rahmani
Mohammed
M
Spiegel
Sarah
S
Koumenis
Costas
C
Graf
Martin
M
Curiel
David T
DT
Grant
Steven
S
Fisher
Paul B
PB
Dent
Paul
P
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
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