Abstract
Abstract It recognized that agents that generate reactive oxygen species (ROS) 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 17AAG, As2O3 or 4HPR, and which correlated with enhanced cell killing. Knock down of CD95 or expression of 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 indicates 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5390. doi:10.1158/1538-7445.AM2011-5390
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