title: PERK-dependent regulation of ceramide synthase 6 and thioredoxin play a key role in mda-7/IL-24-induced killing of primary human glioblastoma multiforme cells.
abstract: Melanoma differentiation associated gene-7(mda-7) encodes IL-24, a cytokine that can selectively trigger apoptosis in transformed cells. Recombinant mda-7 adenovirus (Ad.mda-7) effectively kills glioma cells, offering a novel gene therapy strategy to address deadly brain tumors. In this study, we defined the proximal mechanisms by which Ad-mda-7 kills glioma cells. Key factors implicated included activation of the endoplasmic reticulum stress kinase protein kinase R-like endoplasmic reticulum kinase (PERK), Ca(++) elevation, ceramide generation and reactive oxygen species (ROS) production. PERK inhibition blocked ceramide or dihydroceramide generation, which were critical for Ca(++) induction and subsequent ROS formation. Activation of autophagy and cell death relied upon ROS formation, the inhibition of which ablated Ad.mda-7-killing activity. In contrast, inhibiting TRX induced by Ad.MDA-7 enhanced tumor cytotoxicity and improved animal survival in an orthotopic tumor model. Our findings indicate that mda-7/IL-24 induces an endoplasmic reticulum stress response that triggers production of ceramide, Ca(2+), and ROS, which in turn promote glioma cell autophagy and cell death.
authors.affiliation: Department of Biochemistry and Molecular Biology, VCU Institute of Molecular Medicine, Neurosurgery, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298-0035, USA.
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Hamed
authors.forename: Jeremy
authors.initials: J
authors.lastname: Allegood
authors.forename: Clint
authors.initials: C
authors.lastname: Mitchell
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: William C
authors.initials: WC
authors.lastname: Broaddus
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*; D000099180:Interleukin-24; D000099156:Superoxide Dismutase 2
chemical_list: D002118:Calcium; D002518:Ceramides; D007378:Interleukins; D010088:Oxidoreductases; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D013879:Thioredoxins; D019892:eIF-2 Kinase; D000099180:Interleukin-24; D000099156:Superoxide Dismutase 2; C109343:dihydroceramide; C108138:dihydroceramide desaturase