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Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression

Oncogene volume 19, pages 4604–4610 (2000)Cite this article

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.

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Acknowledgements

Supported from the Jeffrey Miller Neuro-Oncology Research Fund (MA Grotzer.)

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  1. Michael A Grotzer

    Present address: University Children's Hospital of Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland

Authors and Affiliations

  1. Division of Oncology, Abramson Research Building, The Children's Hospital of Philadelphia, 3400 Civic Center Boulevard, 19104, Pennsylvania PA, USA

    Michael A Grotzer, Angelika Eggert, Tycho J Zuzak, Anna J Janss, Sunil Marwaha, Barbara R Wiewrodt, Naohiko Ikegaki, Garrett M Brodeur & Peter C Phillips

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Grotzer, M., Eggert, A., Zuzak, T. et al. Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 19, 4604–4610 (2000). https://doi.org/10.1038/sj.onc.1203816

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