RT Journal Article
SR Electronic
T1 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
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 368
OP 380
DO 10.1124/mol.110.069484
VO 79
IS 3
A1 Margaret A. Park
A1 Hossein A. Hamed
A1 Clint Mitchell
A1 Nichola Cruickshanks
A1 Rupesh Dash
A1 Jeremy Allegood
A1 Igor P. Dmitriev
A1 Gary Tye
A1 Besim Ogretmen
A1 Sarah Spiegel
A1 Adly Yacoub
A1 Steven Grant
A1 David T. Curiel
A1 Paul B. Fisher
A1 Paul Dent
YR 2011
UL http://molpharm.aspetjournals.org/content/79/3/368.abstract
AB 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-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.