1. Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression
- Author
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Naohiko Ikegaki, Garrett M. Brodeur, Anna J. Janss, Tycho J. Zuzak, Angelika Eggert, Sunil Marwaha, Barbara R. Wiewrodt, Michael A. Grotzer, and Peter C. Phillips
- Subjects
Cancer Research ,Transcription, Genetic ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Drug Resistance ,Apoptosis ,medicine.disease_cause ,Receptors, Tumor Necrosis Factor ,TNF-Related Apoptosis-Inducing Ligand ,Jurkat Cells ,Tumor Cells, Cultured ,Neuroectodermal Tumors, Primitive ,DNA (Cytosine-5-)-Methyltransferases ,RNA, Neoplasm ,Cycloheximide ,Enzyme Inhibitors ,Child ,Receptor ,Protein Synthesis Inhibitors ,Regulation of gene expression ,Caspase 8 ,Membrane Glycoproteins ,Intracellular Signaling Peptides and Proteins ,Caspase 9 ,Recombinant Proteins ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Caspases ,Enzyme Induction ,Azacitidine ,Adult ,Antimetabolites, Antineoplastic ,Biology ,Decitabine ,Glioma ,Genetics ,medicine ,Humans ,RNA, Messenger ,Neuroectodermal tumor ,Molecular Biology ,Tumor Necrosis Factor-alpha ,DNA Methylation ,medicine.disease ,Cell culture ,Immunology ,Cancer research ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Carcinogenesis - Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in adult malignant glioma and various other human solid tumor models but not in normal tissues. To characterize the TRAIL death pathway in childhood primitive neuroectodermal brain tumor (PNET), 8 human PNET cell lines were tested for TRAIL-induced apoptosis. TRAIL-sensitivity of the PNET cell lines was correlated with mRNA expression levels of TRAIL, its agonistic (TRAIL-R1, TRAIL-R2) and antagonistic (TRAIL-R3, TRAIL-R4) receptors, cellular FLICE-like inhibitory protein (cFLIP), caspase-3 and caspase-8. Three of 8 PNET cell lines tested were susceptible to TRAIL-induced apoptosis. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cFLIP. However, all TRAIL-sensitive PNET cell lines expressed caspase-8 mRNA and protein, while none of the five TRAIL-resistant PNET cell lines expressed caspase-8 protein. Treatment with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored mRNA expression of caspase-8 and TRAIL-sensitivity in formerly TRAIL-resistant PNET cells, suggesting that gene methylation inhibits caspase-8 transcription in these cells. We conclude, that loss of caspase-8 mRNA is an important mechanism of TRAIL-resistance in PNET cells. Treatment with recombinant soluble TRAIL, possibly in combination with methyltransferase inhibitors, represents a promising therapeutic approach for PNET that deserves further investigation.
- Published
- 2000
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