TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways.
Brain Pathol
; 13(4): 539-53, 2003 Oct.
Article
em En
| MEDLINE
| ID: mdl-14655759
ABSTRACT
Many malignant glioma cells express death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL-induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase-8-initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild-type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to downregulate caspase-8 inhibitor c-FLIP(S) (the short form of cellular Fas-associated death domain-fike interleukin-1-converting enzyme-inhibitory protein) and up-regulate Bak, a pro-apoptotic Bcl-2 family member, independently of cell's TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
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Transdução de Sinais
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Fator de Necrose Tumoral alfa
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Apoptose
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Peptídeos e Proteínas de Sinalização Intracelular
Idioma:
En
Revista:
Brain Pathol
Assunto da revista:
CEREBRO
/
PATOLOGIA
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
Canadá