Abstract
Resistance of tumors to treatment with cytotoxic drugs, irradiation or immunotherapy may be due to disrupted apoptosis programs. Here, we report in a variety of different tumor cells including Ewing tumor, neuroblastoma, malignant brain tumors and melanoma that caspase-8 expression acts as a key determinant of sensitivity for apoptosis induced by death-inducing ligands or cytotoxic drugs. In tumor cell lines resistant to TRAIL, anti-CD95 or TNFα, caspase-8 protein and mRNA expression was decreased or absent without caspase-8 gene loss. Methylation-specific PCR revealed hypermethylation of caspase-8 regulatory sequences in cells with impaired caspase-8 expression. Treatment with the demethylation agent 5-Aza-2′-deoxycytidine (5-dAzaC) reversed hypermethylation of caspase-8 resulting in restoration of caspase-8 expression and recruitment and activation of caspase-8 at the CD95 DISC upon receptor cross-linking thereby sensitizing for death receptor-, and importantly, also for drug-induced apoptosis. Inhibition of caspase-8 activity also inhibited apoptosis sensitization by 5-dAzaC. Similar to demethylation, introduction of caspase-8 by gene transfer sensitized for apoptosis induction. Hypermethylation of caspase-8 was linked to reduced caspase-8 expression in different tumor cell lines in vitro and, most importantly, also in primary tumor samples. Thus, these findings indicate that re-expression of caspase-8, e.g. by demethylation or caspase-8 gene transfer, might be an effective strategy to restore sensitivity for chemotherapy- or death receptor-induced apoptosis in various tumors in vivo.
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Acknowledgements
We thank PH Krammer (DKFZ, Heidelberg, Germany) for anti-FLICE antibody, T Pietsch (University of Bonn, Bonn, Germany) for medulloblastoma tumor samples and E Alnemri (Philadelphia, PA, USA) for dominant negative caspase-8 cDNA. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Forschung und Technologie, Bonn, the Deutsche Leukämieforschungshilfe and the Wilhelm Sander-Stiftung.
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Fulda, S., Küfer, M., Meyer, E. et al. Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene 20, 5865–5877 (2001). https://doi.org/10.1038/sj.onc.1204750
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DOI: https://doi.org/10.1038/sj.onc.1204750