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A serotype 5/3 adenovirus expressing MDA-7/IL-24 infects renal carcinoma cells and promotes toxicity of agents that increase ROS and ceramide levels Park MA; Hamed HA; Mitchell C; Cruickshanks N; Dash R; Allegood J; Dmitriev IP; Tye G; Ogretmen B; Spiegel S; Yacoub A; Grant S; Curiel DT; Fisher PB; Dent PMol Pharmacol 2011[Mar]; 79 (3): 368-80Agents that generate reactive oxygen species (ROS) are recognized to enhance MDA-7/IL-24 lethality. The present studies focused on clarifying how such agents enhanced MDA-7/IL-24 toxicity in renal cell carcinoma cells (RCCs). Infection of RCCs with a tropism-modified serotype 5/3 adenovirus expressing MDA-7/IL-24 (Ad.5/3-mda-7) caused plasma membrane clustering of CD95 and CD95 association with pro-caspase 8, effects that were enhanced by combined exposure to 17-N-allylamino-17-demethoxygeldanamycin (17AAG), As(2)O(3), or fenretinide and that correlated with enhanced cell killing. Knockdown of CD95 or expression of cellular FADD (Fas-associated protein with death domain)-like interleukin-1beta-converting enzyme inhibitory protein, short form (c-FLIP-s) blocked enhanced killing. Inhibition of ROS generation, elevated cytosolic Ca(2+), or de novo ceramide synthesis blocked Ad.5/3-mda-7 +/- agent-induced CD95 activation and the enhancement of apoptosis. Ad.5/3-mda-7 increased ceramide levels in a PERK-dependent fashion that were responsible for elevated cytosolic Ca(2+) levels that promoted ROS generation; 17AAG did not further enhance cytokine-induced ceramide generation. In vivo, infection of RCC tumors with Ad.5/3-mda-7 suppressed the growth of infected tumors that was enhanced by exposure to 17AAG. Our data indicate that in RCCs, Ad.5/3-mda-7-induced ceramide generation plays a central role in tumor cell killing and inhibition of multiple signaling pathways may have utility in promoting MDA-7/IL-24 lethality in renal cancer.|Adenoviridae/*metabolism/physiology[MESH]|Animals[MESH]|Arsenic Trioxide[MESH]|Arsenicals/pharmacology[MESH]|Benzoquinones/pharmacology[MESH]|Blotting, Western[MESH]|Carcinoma, Renal Cell/chemistry/metabolism/*virology[MESH]|Cell Line, Tumor[MESH]|Ceramides/analysis/*metabolism[MESH]|Dose-Response Relationship, Drug[MESH]|Electrophoresis, Polyacrylamide Gel[MESH]|Female[MESH]|Flow Cytometry[MESH]|Humans[MESH]|Interleukins/*biosynthesis/metabolism/physiology[MESH]|Kidney Neoplasms/chemistry/metabolism/*virology[MESH]|Lactams, Macrocyclic/pharmacology[MESH]|Mice[MESH]|Mice, Nude[MESH]|Oxides/pharmacology[MESH]|Reactive Oxygen Species/analysis/*metabolism[MESH]|Transfection[MESH] |
