Acta Neuropathologica

, Volume 117, Issue 4, pp 445–456 | Cite as

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

  • David Capper
  • Timo Gaiser
  • Christian Hartmann
  • Antje Habel
  • Wolf Mueller
  • Christel Herold-Mende
  • Andreas von Deimling
  • Markus David Siegelin
Original Paper

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.

Keywords

Stem-cell-like glioma cells Caspase-8 TRAIL Apoptosis CD133 

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

Notes

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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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • David Capper
    • 1
  • Timo Gaiser
    • 1
  • Christian Hartmann
    • 1
    • 3
  • Antje Habel
    • 1
  • Wolf Mueller
    • 1
  • Christel Herold-Mende
    • 2
  • Andreas von Deimling
    • 1
    • 3
  • Markus David Siegelin
    • 1
  1. 1.Department of NeuropathologyUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Department of NeurosurgeryUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.Clinical Cooperation Unit NeuropathologyGerman Cancer Center (DKFZ) G380HeidelbergGermany

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