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TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5

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An Erratum to this article was published on 24 February 2011

Abstract

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies. TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far. In the present work, we analyzed cell viability, DISC formation as well as IL-8 and NF–κB activation side by side in responses to TRAIL and agonistic antibodies against DR4 (mapatumumab) and against DR5 (lexatumumab) in pancreatic ductal adenocarcinoma cells. We found that all three reagents are able to activate cell death and pro-inflammatory signaling. Death-inducing signaling complex (DISC) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5, whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors. Notably, blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4. Interestingly, inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death. Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment.

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Acknowledgements

We thank Daniela Berg and Andreas Wicovsky for generation and characterization of TRAIL-receptor-specific antibodies and Fab fragments, Daniela Wesch for help with FACS analyses, and Robin Humphreys at Human Genome Sciences for supporting us with mapatumumab and lexatumumab antibodies. Some of the data are part of the doctoral thesis of Johannes Lemke. This work was supported by the DFG grant SFB 415/A3 given to Holger Kalthoff and DFG grants SCHU733/7-1 and SCHU 733/9-1 given to Stefan Schütze. In addition, the authors have no conflicts of interest to declare. All authors contributed to the preparation of the manuscript.

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Authors and Affiliations

  1. Division of Molecular Oncology, Institute of Experimental Cancer Research, Comprehensive Cancer Center North, UK S-H, Arnold-Heller Str. 3, Haus 17, 24 105, Kiel, Germany

    Johannes Lemke, Andreas Noack, Christian Röder, Holger Kalthoff & Anna Trauzold

  2. Institute of Immunology, UK S-H, Kiel, Germany

    Dieter Adam, Vladimir Tchikov, Uwe Bertsch & Stefan Schütze

  3. Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, 97070, Würzburg, Germany

    Harald Wajant

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  1. Johannes Lemke
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An erratum to this article can be found at http://dx.doi.org/10.1007/s00109-011-0738-2

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Lemke, J., Noack, A., Adam, D. et al. TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5. J Mol Med 88, 729–740 (2010). https://doi.org/10.1007/s00109-010-0619-0

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