Original Paper | Published:

Caspase-10: a molecular switch from cell-autonomous apoptosis to communal cell death in response to chemotherapeutic drug treatment

Cell Death and Differentiation volume 25, pages 340352 (2018) | Download Citation

Edited by D Vaux

Abstract

The mechanisms of how chemotherapeutic drugs lead to cell cycle checkpoint regulation and DNA damage repair are well understood, but how such signals are transmitted to the cellular apoptosis machinery is less clear. We identified a novel apoptosis-inducing complex, we termed FADDosome, which is driven by ATR-dependent caspase-10 upregulation. During FADDosome-induced apoptosis, cFLIPL is ubiquitinated by TRAF2, leading to its degradation and subsequent FADD-dependent caspase-8 activation. Cancer cells lacking caspase-10, TRAF2 or ATR switch from this cell-autonomous suicide to a more effective, autocrine/paracrine mode of apoptosis initiated by a different complex, the FLIPosome. It leads to processing of cFLIPL to cFLIPp43, TNF-α production and consequently, contrary to the FADDosome, p53-independent apoptosis. Thus, targeting the molecular levers that switch between these mechanisms can increase efficacy of treatment and overcome resistance in cancer cells.

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Acknowledgements

We thank Greg Brooke for helpful discussions and Jigyasa Arora, Alex Menzies, Alice Godden, Rui Yu, Chirlei Klein for technical assistance and John Norton for support with the RNA-Seq experiment. RMZ was supported by an Emmy-Noether grant (ZW60/2), a Marie-Curie Excellence grant (MIST) and an RTN grant (ApopTrain).

Author contributions

AM, LD, SJ, YM, LH, SMA performed experiments; AM and RMZ conceived and designed this study; analysed and interpreted data; wrote the manuscript. All authors read and approved the final manuscript.

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Affiliations

  1. School of Biological Sciences, Cancer and Stem Cell Biology Group, University of Essex, Colchester CO4 3SQ, UK

    • Andrea Mohr
    • , Sylwia Jencz
    • , Yasamin Mehrabadi
    • , Lily Houlden
    •  & Ralf M Zwacka
  2. National Centre for Biomedical Engineering Science, National University of Ireland Galway, Galway, Ireland

    • Laura Deedigan
    •  & Stella-Maris Albarenque
  3. School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK

    • Lily Houlden

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Ralf M Zwacka.

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DOI

https://doi.org/10.1038/cdd.2017.164

Supplementary Information accompanies this paper on Cell Death and Differentiation website (http://www.nature.com/cdd)