Journal
MOLECULAR PHARMACOLOGY
Volume 79, Issue 3, Pages 368-380Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.110.069484
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Funding
- National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK52825]
- National Institutes of Health National Cancer Institute [R01-CA108325, R01-CA141703, R01-CA150214, R01-CA63753, R01-CA77141, R01-CA097318, R01-CA127641, R01-CA134721, P01-CA104177]
- Jim Valvano V foundation
- Department of Defense [DAMD17-03-1-0262]
- Leukemia Society of America [6405-97]
- Samuel Waxman Cancer Research Foundation
- National Foundation for Cancer Research
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Agents 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), As2O3, 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-1 beta-converting enzyme inhibitory protein, short form (c-FLIP-s) blocked enhanced killing. Inhibition of ROS generation, elevated cytosolic Ca2+, 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 Ca2+ 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.
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