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lüll 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 Yacoub A; Hamed HA; Allegood J; Mitchell C; Spiegel S; Lesniak MS; Ogretmen B; Dash R; Sarkar D; Broaddus WC; Grant S; Curiel DT; Fisher PB; Dent PCancer Res 2010[Feb]; 70 (3): 1120-9Melanoma 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.|Animals[MESH]|Autophagy[MESH]|Blotting, Western[MESH]|Calcium/metabolism[MESH]|Cell Line[MESH]|Cell Line, Tumor[MESH]|Cell Survival/drug effects[MESH]|Ceramides/metabolism[MESH]|Glioblastoma/genetics/pathology/therapy[MESH]|Humans[MESH]|Interleukins/genetics/*metabolism[MESH]|Mass Spectrometry[MESH]|Mice[MESH]|Mutation[MESH]|Oxidoreductases/genetics/*metabolism[MESH]|RNA Interference[MESH]|Reactive Oxygen Species/metabolism[MESH]|Superoxide Dismutase/metabolism[MESH]|Thioredoxins/genetics/*metabolism[MESH]|Transfection[MESH]|Xenograft Model Antitumor Assays[MESH]|eIF-2 Kinase/genetics/*metabolism[MESH] |