Research Article | Published:

Blood, Lymphatics, Immune System, Stem Cells

RIP1 expression is necessary for CD30-mediated cell death induction in anaplastic large-cell lymphoma cells

Laboratory Investigation volume 93, pages 677689 (2013) | Download Citation

Abstract

CD30, a member of the tumor necrosis factor receptor (TNFR) superfamily, is consistently expressed by tumor cells of anaplastic large-cell lymphoma (ALCL). CD30 stimulation induces massive caspase-dependent cell death of ALCL cells in case of canonical NFκB inhibition or proteasome inhibition. However, CD30, a TNFR lacking a death domain (DD), is unable to recruit a death inducing complex containing TRADD (TNFR1-associated DD-protein) or FADD (FAS-associated DD-domain protein) together with the receptor-interacting protein 1 (RIP1) and caspase-8. Thus, the mechanism explaining CD30-induced cell death of lymphocytes remains obscure. Here, we demonstrate that blockage of RIP1 by siRNA or pharmacological inhibition of RIP1 by Necrostatin-1 almost completely prevented CD30-induced cell death. In addition, we revealed CD30-induced accumulation of RIP1 at the cytoplasma membrane of NFκB-inhibited ALCL cells by confocal laser scanning microscopy. Finally, primary ALCL cases can be subdivided into two groups based on the presence or absence of RIP1 as revealed by immunohistology. Taken together, our study identified RIP1 as a crucial mediator of CD30-induced cell death that bears features of apoptosis as well as necroptosis. RIP1 expression in ALCL tumor cells might eligible for the therapeutic application of CD30 antibodies in combination with NFκB/proteasome inhibitors that should result in CD30-induced cell death.

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Acknowledgements

We are grateful to Dr Dido Lenze for her excellent help with Partek software-based CEL-file data analysis of Affymetrix Human Genome U133Plus 2.0 Arrays. This work was supported by the Deutsche Forschungsgemeinschaft (DU370/3-1). The IAP-antagonist (Smac mimetic) BV6 was kindly provided by Dr Vucic, Genentech, USA.

Author information

Author notes

    • Michael Hummel
    •  & Horst Dürkop

    These authors contributed equally to this work.

Affiliations

  1. Department of Experimental Haematology, Institute of Pathology, Charité—University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany

    • Burkhard Hirsch
    • , Edda von der Wall
    •  & Michael Hummel
  2. Pathodiagnostik, Berlin, Germany

    • Horst Dürkop

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Burkhard Hirsch.

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DOI

https://doi.org/10.1038/labinvest.2013.50

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