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

被引：84

作者：

Capper, David ^{[1
]}

Gaiser, Timo ^{[1
]}

Hartmann, Christian ^{[1
,3
]}

Habel, Antje ^{[1
]}

Mueller, Wolf ^{[1
]}

Herold-Mende, Christel ^{[2
]}

von Deimling, Andreas ^{[1
,3
]}

Siegelin, Markus David ^{[1
]}

机构：

[1] Univ Heidelberg Hosp, Dept Neuropathol, D-69120 Heidelberg, Germany

[2] Univ Heidelberg Hosp, Dept Neurosurg, D-69120 Heidelberg, Germany

[3] German Canc Ctr DKFZ G380, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany

来源：

ACTA NEUROPATHOLOGICA | 2009年 / 117卷 / 04期

关键词：

Stem-cell-like glioma cells; Caspase-8; TRAIL; Apoptosis; CD133; TRAIL-INDUCED APOPTOSIS; HUMAN ASTROCYTOMA-CELLS; MEDIATED APOPTOSIS; DNA METHYLATION; UP-REGULATION; C-FLIP; EXPRESSION; SENSITIZES; DEATH; INHIBITION;

D O I：

10.1007/s00401-009-0494-3

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

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.

引用

页码：445 / 456

页数：12

共 39 条

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