Source:http://linkedlifedata.com/resource/pubmed/id/11406564
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
12
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| pubmed:dateCreated |
2001-6-14
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| pubmed:abstractText |
Fas-mediated apoptosis proceeds though mitochondria-dependent or -independent pathways and is deficient in drug-resistant cells. Neuroblastoma, a common pediatric malignancy, often develops drug-resistance and has a silenced caspase 8 (FLICE) gene, which has been associated with Fas- and drug-resistance. We report that besides caspase 8, which was absent in approximately one-third of 26 neuroblastoma cases in this study, other proteins such as bcl-2 and FLICE-inhibitory protein (FLIP), are equally important in conferring Fas-resistance to neuroblastoma cells. Both bcl-2 and FLIP were frequently expressed in neuroblastoma tissues. Our in vitro studies showed that FLIP was recruited to the death-inducing signaling complex and interfered with the recruitment of caspase 8 in neuroblastoma cells. bcl-2 inhibited the activation of the mitochondria; but it also lowered the free cytoplasmic levels of caspase 8 by binding and sequestering it, thus acting through a novel antiapoptotic mechanism upstream of the mitochondria. In vitro down-regulation of bcl-2 with antisense oligonucleotides allowed the release of cytochrome c from mitochondria and the activation of caspases 8 and 3 upon Fas activation as well as sensitized neuroblastoma cells to Fas-mediated apoptosis. Down-regulation of FLIP had only a modest apoptotic effect because of the coexistent mitochondrial block. However, combined treatment with bcl-2 and FLIP antisense oligonucleotides had a statistically significant synergistic effect reversing Fas-resistance in neuroblastoma cells in vitro. These data indicate that Fas-mediated apoptosis in neuroblastoma cells is mitochondria-dependent and inhibited both at the mitochondrial level and at the level of caspase 8 activation. Thus, gene-targeting therapies for bcl-2 and FLIP may reverse Fas-resistance and prove useful in the treatment of drug-resistant neuroblastomas.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD95,
http://linkedlifedata.com/resource/pubmed/chemical/CASP8 and FADD-Like Apoptosis...,
http://linkedlifedata.com/resource/pubmed/chemical/CASP8 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CASP9 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CFLAR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 8,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 9,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome c Group,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Oligonucleotides, Antisense,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jun
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| pubmed:issn |
0008-5472
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
15
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| pubmed:volume |
61
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
4864-72
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| pubmed:dateRevised |
2006-11-15
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| pubmed:meshHeading |
pubmed-meshheading:11406564-Adolescent,
pubmed-meshheading:11406564-Antigens, CD95,
pubmed-meshheading:11406564-Apoptosis,
pubmed-meshheading:11406564-CASP8 and FADD-Like Apoptosis Regulating Protein,
pubmed-meshheading:11406564-Carrier Proteins,
pubmed-meshheading:11406564-Caspase 8,
pubmed-meshheading:11406564-Caspase 9,
pubmed-meshheading:11406564-Caspases,
pubmed-meshheading:11406564-Child,
pubmed-meshheading:11406564-Child, Preschool,
pubmed-meshheading:11406564-Cytochrome c Group,
pubmed-meshheading:11406564-Enzyme Activation,
pubmed-meshheading:11406564-Humans,
pubmed-meshheading:11406564-Infant,
pubmed-meshheading:11406564-Infant, Newborn,
pubmed-meshheading:11406564-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:11406564-Mitochondria,
pubmed-meshheading:11406564-Neuroblastoma,
pubmed-meshheading:11406564-Oligonucleotides, Antisense,
pubmed-meshheading:11406564-Proto-Oncogene Proteins c-bcl-2
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| pubmed:year |
2001
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| pubmed:articleTitle |
Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2.
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| pubmed:affiliation |
Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
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| pubmed:publicationType |
Journal Article
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