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

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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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Abbreviations

IAP:

Inhibitor of apoptosis protein

TRAIL:

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand

SCG:

Stem-cell-like glioma cells

NSCG:

Non-stem-cell-like glioma cells

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Acknowledgments

We thank Volker Ehemann for performing flow cytometry. This work was supported by a grant from the PostDoc programme to Markus Siegelin of the University of Heidelberg.

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Authors and Affiliations

  1. Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Germany

    David Capper, Timo Gaiser, Christian Hartmann, Antje Habel, Wolf Mueller, Andreas von Deimling & Markus David Siegelin

  2. Department of Neurosurgery, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Christel Herold-Mende

  3. Clinical Cooperation Unit Neuropathology, German Cancer Center (DKFZ) G380, Im Neuenheimer Feld 220, 69120, Heidelberg, Germany

    Christian Hartmann & Andreas von Deimling

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  1. David Capper
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  2. Timo Gaiser
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Correspondence to Markus David Siegelin.

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Capper, D., Gaiser, T., Hartmann, C. et al. Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation. Acta Neuropathol 117, 445–456 (2009). https://doi.org/10.1007/s00401-009-0494-3

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  • DOI: https://doi.org/10.1007/s00401-009-0494-3

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