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Sensitization of melanoma cells to TRAIL by UVB-induced and NF-κB-mediated downregulation of xIAP

Oncogene volume 28, pages 345–362 (2009)Cite this article

Abstract

Effective treatment of malignant melanoma with the tumor-selective death ligand tumor necrosis-related apoptosis-inducing ligand (TRAIL) is curtailed by the fact that many melanoma cell lines are a priori resistant against TRAIL-induced apoptosis. By investigating 18 melanoma cell lines, we show that TRAIL susceptibility is completely independent of the tumor progression stage but can be positively stimulated by co-exposure to a sublethal ultraviolet B light (UVB) dose, providing an excellent tool to study the mechanism underlying TRAIL resistance. TRAIL resistance could be linked to the ratio of x-linked inhibitor of apoptosis proteins (xIAP) and caspase-3 levels within the cell. UVB-induced sensitization coincides with enhanced xIAP degradation, allowing full caspase-3 processing and activation. It is also accompanied by concomitant IκBα degradation, resulting in nuclear factor-κB (NF-κB)-dependent transcriptional repression of xIAP. Loss of xIAP in turn was reduced upon overexpression of an IκBα super-repressor, thus NF-κB activation seems to be responsible for differential regulation of xIAP and consequently determines TRAIL susceptibility. As xIAP-mediated blockade of apoptosis seems to be the dominant cause of TRAIL resistance of all melanoma cell lines investigated here, our data suggest that direct chemical xIAP inhibition or combination treatment with DNA-damaging agents may offer new therapeutic strategies to generally sensitize melanoma toward TRAIL-induced apoptosis.

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Acknowledgements

We thank Amgen/Genentech (Seattle, USA) for providing TRAIL antibodies. We are grateful to F Meier (Department of Dermato-Oncology, University of Tübingen) for providing melanoma cell lines and melanocytes, H Walczak (Tumour Immunology Unit, Imperial College London) for supplying iz-TRAIL and to H Kashkar (Institute for Medical Microbiology, University of Cologne) for the xIAP-pEGFPC3 construct. This study was funded by Deutsche Krebshilfe 106699.

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  1. Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany

    B Thayaparasingham, A Kunz, N Peters & D Kulms

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  1. B Thayaparasingham
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  2. A Kunz
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  3. N Peters
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  4. D Kulms
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Correspondence to D Kulms.

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Thayaparasingham, B., Kunz, A., Peters, N. et al. Sensitization of melanoma cells to TRAIL by UVB-induced and NF-κB-mediated downregulation of xIAP. Oncogene 28, 345–362 (2009). https://doi.org/10.1038/onc.2008.397

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