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Drug-mediated sensitization to TRAIL-induced apoptosis in caspase-8-complemented neuroblastoma cells proceeds via activation of intrinsic and extrinsic pathways and caspase-dependent cleavage of XIAP, Bcl-xL and RIP

Oncogene volume 23, pages 5415–5425 (2004)Cite this article

Abstract

Neuroblastoma (NB) is a childhood neoplasm which heterogeneous behavior can be explained by differential regulation of apoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces rapid apoptosis in most tumor cells and thus represents a promising anticancer agent. We have reported silencing of caspase-8 expression in highly malignant NB cells as a possible mechanism of resistance to TRAIL-induced apoptosis. To explore the particular contribution of caspase-8 in such resistance, retroviral-mediated stable caspase-8 expression was induced in the IGR-N91 cells. As a result, sensitivity to TRAIL was fully restored in the caspase-8-complemented cells. TRAIL-induced cell death could be further enhanced by cotreatment of IGR-N91-C8 and SH-EP cells with cycloheximide or subtoxic concentrations of chemotherapeutic drugs in a caspase-dependent manner. Sensitization to TRAIL involved enhanced death receptor DR5 expression, activation of Bid and the complete caspases cascade. Interestingly, combined treatments also enhanced the cleavage-mediated inactivation of antiapoptotic molecules, XIAP, Bcl-xL and RIP.

Our results show that restoration of active caspase-8 expression in a caspase-8-deficient NB cell line is necessary and sufficient to fully restore TRAIL sensitivity. Moreover, the synergistic effect of drugs and TRAIL results from activation of the caspase cascade via a mitochondrial pathway-mediated amplification loop and from the inactivation of apoptosis inhibitors.

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Abbreviations

CHX:

cycloheximide

DISC:

death-inducing signalling complex

DOX:

doxorubicin

IAP:

inhibitor of apoptosis

NB:

neuroblastoma

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

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Acknowledgements

We thank O Micheau and J Tschopp for helpful advice as well as for providing us with TRAIL, the caspase-8a cDNA sequence and plasmids. We also thank D Cefaï for collaboration in the retroviral infections and P Batar for helping us with the FACS analyses.

This work was supported by grants from the Swiss Cancer League (to NG, KFS 1086-09-2000), from the Swiss National Scientific Foundation (to NG, 3100-067918.02) and from the FORCE foundation.

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  1. Pediatric Department CHUV, Pediatric Oncology Research, Lausanne, CH-1011, Switzerland

    Annick Mühlethaler-Mottet, Katia Balmas Bourloud, Katya Auderset, Jean-Marc Joseph & Nicole Gross

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  1. Annick Mühlethaler-Mottet
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Correspondence to Nicole Gross.

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Mühlethaler-Mottet, A., Bourloud, K., Auderset, K. et al. Drug-mediated sensitization to TRAIL-induced apoptosis in caspase-8-complemented neuroblastoma cells proceeds via activation of intrinsic and extrinsic pathways and caspase-dependent cleavage of XIAP, Bcl-xL and RIP. Oncogene 23, 5415–5425 (2004). https://doi.org/10.1038/sj.onc.1207704

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