RESUMEN

Tumors have developed several forms of resistance to receptor-induced cell death. Here, we show that malignant mesothelial (MM) cell lines as well as primary MM cells and normal mesothelial (NM) cells express Fas and TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. We found that, although Fas expression levels are comparable, only MM cells are resistant to cell death. Furthermore, MM cells show resistance to TRAIL-induced apoptosis. Caspase-8 (FLICE) is not activated by death receptors triggering in malignant cells whereas it is well activated by nonreceptor stimuli, such as UV radiation. We found that FLIP (FLICE-Inhibitory Protein) is constitutively expressed in all MM cell lines and is more expressed in primary MM cells than in NM cells. Knockdown of FLIP expression in MM cell lines, by a FLIPsiRNA, re-established the normal response to apoptosis induced by Fas or DR4/DR5, which was blocked by pretreatment with the caspase-8 inhibitor z-IETD-fmk. These results indicate that MM cells develop an intrinsic resistance to apoptosis induced by death receptors upregulating the expression of the antiapoptotic protein c-FLIP.

Asunto(s)

Apoptosis/fisiología , Caspasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Mesotelioma/patología , Receptores del Factor de Necrosis Tumoral/fisiología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Secuencia de Bases , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Caspasa 8 , Inhibidores de Caspasas , Línea Celular , Línea Celular Tumoral , Inhibidores de Cisteína Proteinasa/farmacología , Cartilla de ADN , Epitelio/fisiología , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Mesotelioma/genética , Oligopéptidos/farmacología , Ploidias , ARN Interferente Pequeño/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Receptor fas/fisiología