title: Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation.
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.
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 220, 69120, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.forename: Timo
authors.initials: T
authors.lastname: Gaiser
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Antje
authors.initials: A
authors.lastname: Habel
authors.forename: Wolf
authors.initials: W
authors.lastname: Mueller
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Markus David
authors.initials: MD
authors.lastname: Siegelin
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000077209:Decitabine; D003513:Cycloheximide; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D001374:Azacitidine