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TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation.
Puduvalli, V K; Sampath, D; Bruner, J M; Nangia, J; Xu, R; Kyritsis, A P.
Afiliación
  • Puduvalli VK; Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 7700, USA. vpuduval@mdanderson.org
Apoptosis ; 10(1): 233-43, 2005 Jan.
Article en En | MEDLINE | ID: mdl-15711939
Patients with malignant gliomas have a poor prognosis and new treatment paradigms are needed against this disease. TRAIL/Apo2L selectively induces apoptosis in malignant cells sparing normal cells and is hence of interest as a potential therapeutic agent against gliomas. To determine the factors that modulate sensitivity to TRAIL, we examined the differences in TRAIL-activated signaling pathways in glioma cells with variable sensitivities to the agent. Apoptosis in response to TRAIL was unrelated to DR5 expression or endogenous p53 status in a panel of 8 glioma cell lines. TRAIL activated the extrinsic (cleavage of caspase-8, caspase-3 and PARP) and mitochondrial apoptotic pathways and reduced FLIP levels. It also induced caspase-dependent JNK activation, which did not influence TRAIL-induced apoptosis. Because the pro-survival PI3K/Akt pathway is highly relevant to gliomas, we assessed whether Akt could protect against TRAIL-induced apoptosis. Pretreatment with SH-6, a novel Akt inhibitor, enhanced TRAIL-induced apoptosis, suggesting a protective role for Akt. Conversely, TRAIL induced caspase-dependent cleavage of Akt neutralizing its anti-apoptotic effects. These results demonstrate that TRAIL-induced apoptosis in gliomas involves both activation of death pathways and downregulation of survival pathways. Additional studies are warranted to determine the therapeutic potential of TRAIL against gliomas.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glicoproteínas de Membrana / Proteínas Proto-Oncogénicas / Factor de Necrosis Tumoral alfa / Proteínas Serina-Treonina Quinasas / Apoptosis / Quinasas de Proteína Quinasa Activadas por Mitógenos / Proteínas Quinasas JNK Activadas por Mitógenos / Glioma Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Apoptosis Año: 2005 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Glicoproteínas de Membrana / Proteínas Proto-Oncogénicas / Factor de Necrosis Tumoral alfa / Proteínas Serina-Treonina Quinasas / Apoptosis / Quinasas de Proteína Quinasa Activadas por Mitógenos / Proteínas Quinasas JNK Activadas por Mitógenos / Glioma Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Apoptosis Año: 2005 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos