Acta Neuropathologica

, Volume 117, Issue 4, pp 445–456

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

Authors

  • David Capper
    • Department of NeuropathologyUniversity Hospital Heidelberg
  • Timo Gaiser
    • Department of NeuropathologyUniversity Hospital Heidelberg
  • Christian Hartmann
    • Department of NeuropathologyUniversity Hospital Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Center (DKFZ) G380
  • Antje Habel
    • Department of NeuropathologyUniversity Hospital Heidelberg
  • Wolf Mueller
    • Department of NeuropathologyUniversity Hospital Heidelberg
  • Christel Herold-Mende
    • Department of NeurosurgeryUniversity Hospital Heidelberg
  • Andreas von Deimling
    • Department of NeuropathologyUniversity Hospital Heidelberg
    • Clinical Cooperation Unit NeuropathologyGerman Cancer Center (DKFZ) G380
    • Department of NeuropathologyUniversity Hospital Heidelberg
Original Paper

DOI: 10.1007/s00401-009-0494-3

Cite this article as:
Capper, D., Gaiser, T., Hartmann, C. et al. Acta Neuropathol (2009) 117: 445. doi:10.1007/s00401-009-0494-3

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 cellsCaspase-8TRAILApoptosisCD133

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

Copyright information

© Springer-Verlag 2009