Abstract | BACKGROUND: Many tumor cells are resistant to Apo2L/TRAIL-induced apoptosis in the absence of inhibitors of protein synthesis. Apo2L/TRAIL, in addition to induction of apoptosis, may therefore also activate survival pathways. METHODS: Here we investigated whether such survival pathways mediate resistance to Apo2L.0-induced apoptosis in human glioma cells. RESULTS: Apo2L.0 induced the phosphorylation of ERK1/2, but not of Akt. This effect was unaffected by caspase inhibition. Inhibitors of protein synthesis, PI3 kinase, ERK kinase, NF-kappaB or casein kinase 2 sensitized for Apo2L.0-induced apoptosis to a different extent in a panel of human malignant glioma cell lines. However, none of the sensitizers overcame resistance mediated by ectopic expression of the viral caspase 8 inhibitor, crm-A. Primary glioma cultures were almost completely resistant to Apo2L.0-induced cell death even in the presence of the inhibitors. Caspase-8 was expressed in these cells whereas only weak expression of DR5 was detected. Transient expression of DR5 conferred sensitivity to Apo2L.0. CONCLUSION: These data challenge the view that specific cell lines harbour specific mechanisms of resistance to Apo2L/TRAIL. Weak expression of DR5 in primary glioma might limit the therapeutic application of Apo2L/TRAIL in human glioblastoma patients.
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Authors | Johannes Rieger, Brigitte Frank, Michael Weller, Wolfgang Wick |
Journal | Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
(Cell Physiol Biochem)
Vol. 20
Issue 1-4
Pg. 23-34
( 2007)
ISSN: 1015-8987 [Print] Germany |
PMID | 17595512
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- Recombinant Proteins
- TNF-Related Apoptosis-Inducing Ligand
- Extracellular Signal-Regulated MAP Kinases
- CASP8 protein, human
- Caspase 8
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Topics |
- Apoptosis
(drug effects)
- Caspase 8
(metabolism)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Drug Resistance, Neoplasm
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Glioma
(drug therapy, genetics, metabolism, pathology)
- Humans
- Phosphorylation
- Receptors, TNF-Related Apoptosis-Inducing Ligand
(genetics, metabolism)
- Recombinant Proteins
(genetics, metabolism, pharmacology)
- Signal Transduction
(drug effects)
- TNF-Related Apoptosis-Inducing Ligand
(pharmacology)
- Transfection
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