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.
Mol Pharmacol
; 79(3): 368-80, 2011 Mar.
Article
em En
| MEDLINE
| ID: mdl-21119025
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), 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-1ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Renais
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Ceramidas
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Adenoviridae
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Interleucinas
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Espécies Reativas de Oxigênio
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Neoplasias Renais
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Mol Pharmacol
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos