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MDA-7/IL-24-induced cell killing in malignant renal carcinoma cells occurs by a ceramide/CD95/PERK-dependent mechanism Park MA; Walker T; Martin AP; Allegood J; Vozhilla N; Emdad L; Sarkar D; Rahmani M; Graf M; Yacoub A; Koumenis C; Spiegel S; Curiel DT; Voelkel-Johnson C; Grant S; Fisher PB; Dent PMol Cancer Ther 2009[May]; 8 (5): 1280-91Melanoma 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 present studies focused on clarifying the mechanism(s) by which glutathione S-transferase (GST)-MDA-7 altered cell survival of human renal carcinoma cells in vitro. GST-MDA-7 caused plasma membrane clustering of CD95 and the association of CD95 with procaspase-8. GST-MDA-7 lethality was suppressed by inhibition of caspase-8 or by overexpression of short-form cellular FLICE inhibitory protein, but only weakly by inhibition of cathepsin proteases. GST-MDA-7-induced CD95 clustering (and apoptosis) was blocked by knockdown of acidic sphingomyelinase or, to a greater extent, ceramide synthase-6 expression. GST-MDA-7 killing was, in parallel, dependent on inactivation of extracellular signal-regulated kinase 1/2 and on CD95-induced p38 mitogen-activated protein kinase and c-jun NH(2)-terminal kinase-1/2 signaling. Knockdown of CD95 expression abolished GST-MDA-7-induced phosphorylation of protein kinase R-like endoplasmic reticulum kinase. GST-MDA-7 lethality was suppressed by knockout or expression of a dominant negative protein kinase R-like endoplasmic reticulum kinase that correlated with reduced c-jun NH(2)-terminal kinase-1/2 and p38 mitogen-activated protein kinase signaling and maintained extracellular signal-regulated kinase-1/2 phosphorylation. GST-MDA-7 caused vacuolization of LC3 through a mechanism that was largely CD95 dependent and whose formation was suppressed by knockdown of ATG5 expression. Knockdown of ATG5 suppressed GST-MDA-7 toxicity. Our data show that in kidney cancer cells GST-MDA-7 induces ceramide-dependent activation of CD95, which is causal in promoting an endoplasmic reticulum stress response that activates multiple proapoptotic pathways to decrease survival.|Apoptosis/drug effects[MESH]|Carcinoma, Renal Cell/*pathology[MESH]|Caspase 8/metabolism[MESH]|Cell Line, Transformed[MESH]|Cell Line, Tumor[MESH]|Cell Survival/*drug effects[MESH]|Ceramides/*metabolism[MESH]|Dose-Response Relationship, Drug[MESH]|Humans[MESH]|Interleukins/*metabolism[MESH]|JNK Mitogen-Activated Protein Kinases/metabolism[MESH]|Recombinant Fusion Proteins/metabolism[MESH]|Signal Transduction/drug effects[MESH]|eIF-2 Kinase/*metabolism[MESH]|fas Receptor/*metabolism[MESH]|p38 Mitogen-Activated Protein Kinases/metabolism[MESH] |