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

Margaret A. Park, Hossein A. Hamed, Clint Mitchell, Nichola Cruickshanks, Rupesh Dash, Jeremy Allegood, Igor P. Dmitriev, Gary Tye, Besim Ogretmen, Sarah Spiegel, Adly Yacoub, Steven Grant, David T. Curiel, Paul B. Fisher, Paul Dent

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

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), As2O 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-1β-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.

Original languageEnglish
Pages (from-to)368-380
Number of pages13
JournalMolecular pharmacology
Volume79
Issue number3
DOIs
StatePublished - Mar 2011

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Park, M. A., Hamed, H. A., Mitchell, C., Cruickshanks, N., Dash, R., Allegood, J., Dmitriev, I. P., Tye, G., Ogretmen, B., Spiegel, S., Yacoub, A., Grant, S., Curiel, D. T., Fisher, P. B., & Dent, P. (2011). 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. Molecular pharmacology, 79(3), 368-380. https://doi.org/10.1124/mol.110.069484