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01-04-2009 | Original Paper

Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation

Authors: David Capper, Timo Gaiser, Christian Hartmann, Antje Habel, Wolf Mueller, Christel Herold-Mende, Andreas von Deimling, Markus David Siegelin

Published in: Acta Neuropathologica | Issue 4/2009

Abstract

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising cancer drug. However, many tumours are resistant to TRAIL-based therapies. Glioma cells with stem cell features (SCG), such as CD133 expression and neurosphere formation, have been recently identified to be more resistant to cytotoxic drugs than glioma cells lacking stem-cell-like features (NSCGs). Here we report that SCGs are completely resistant to 100–2,000 ng/ml TRAIL, whereas NSCGs revealed a moderate sensitivity to TRAIL. We found that SCGs exhibited only low levels of caspase-8 mRNA and protein, known to be indispensable for TRAIL-induced apoptosis. In addition, we detected hypermethylation of CASP8 promoter in SCGs, whereas NSCGs exhibited a non-methylated CASP8 promoter. Reexpression of caspase-8 by 5-Aza-2′-deoxycytidine was not sufficient to restore TRAIL sensitivity in SCGs cells, suggesting that additional factors cause TRAIL resistance in SCGs. Our data suggest that therapy with TRAIL, either as monotherapy or in combination with demethylating agents, is not effective in treating glioblastoma because SCGs are not targeted by such treatment.

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Title: Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation
Authors: David Capper
Timo Gaiser
Christian Hartmann
Antje Habel
Wolf Mueller
Christel Herold-Mende
Andreas von Deimling
Markus David Siegelin
Publication date: 01-04-2009
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 4/2009
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-009-0494-3

At a glance: The STEP trials

Springer Medicine

Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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