Abstract

Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.

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Acknowledgements

This work was supported by a Cancer Research UK Programme Foundation award (C40872/A20145) (S.W.G.T.) and a Cancer Research UK studentship. J.L. was supported, in part, by the University of Lyon and by fellowships from Fondation ARC pour la Recherche sur le Cancer and Hospices Civils de Lyon. G.I. was supported by an EMBO long-term postdoctoral fellowship (ALTF 55–2013).C.R.-P. was supported by the Fondation ARC pour la Recherche sur le Cancer and the Agence Nationale de la Recherche (LABEX SIGNALIFE ANR-11-LABX-0028-01). We thank J. Silke (Walter and Eliza Hall Institute), M. Martins (MRC Toxicology Unit), F. Zhang (Massachusetts Institute of Technology), D. Murphy (Beatson Institute) and D. Graczyk (Polish Academy of Sciences) for reagents, A. Keith, B. Clark, T. Gilbey, M. O’Prey (Beatson Institute, UK), D. Vaughan, L. Lapienyte, V. Imbert (Université de Nice-Sophia-Antipolis), M. Hou and C. Thompson (University of Glasgow) for technical assistance. We acknowledge support from Cancer Research UK Glasgow Centre (C596/A18076), the Histology and BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196) and Centre Méditerranéen de Médecine Moléculaire animal facility. Finally, we thank C. Winchester (Beatson Institute) and members of the Tait laboratory for reviewing the manuscript.

Author information

Author notes

    • Barbara Zunino
    •  & Sandeep Dhayade

    These authors contributed equally to this work.

    • Jonathan Lopez
    •  & Gabriel Ichim

    Present address: University of Lyon, Cancer Research Centre of Lyon (CRCL), UMR INSERM 1052 CNRS 5286, Léon Bérard Centre, 28, Rue Laennec, 69008 Lyon, France (J.L., G.I.).

Affiliations

  1. Cancer Research UK Beatson Institute, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK

    • Evangelos Giampazolias
    • , Barbara Zunino
    • , Sandeep Dhayade
    • , Florian Bock
    • , Catherine Cloix
    • , Kai Cao
    • , Alba Roca
    • , Jonathan Lopez
    • , Gabriel Ichim
    • , Loic Fort
    • , Emma Woodham
    • , Laura Machesky
    • , Kevin M. Ryan
    • , Karen Blyth
    •  & Stephen W. G. Tait
  2. Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK

    • Evangelos Giampazolias
    • , Florian Bock
    • , Catherine Cloix
    • , Kai Cao
    • , Alba Roca
    • , Jonathan Lopez
    • , Gabriel Ichim
    •  & Stephen W. G. Tait
  3. Université Côte d’Azur, Inserm, C3M, France

    • Emma Proïcs
    • , Camila Rubio-Patiño
    •  & Jean-Ehrland Ricci
  4. Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France

    • Nader Yatim
    •  & Matthew L. Albert
  5. Molecular & Cellular Biology Program and Department of Immunology, University of Washington, 750 Republican Street, Seattle, Washington 98109, USA

    • Susana Orozco
    •  & Andrew Oberst
  6. Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, UCL, London WC1E 6BT, UK

    • Lucia Taraborrelli
    • , Nieves Peltzer
    •  & Henning Walczak
  7. Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy

    • Daniele Lecis
  8. Department of Cancer Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Matthew L. Albert
  9. Centre for Immunobiology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK

    • Simon Milling

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Contributions

E.G. and S.W.G.T. conceived the study, and designed the work plan together with K.B., J.-E.R. and S.M. Experimental work: E.G., B.Z., S.D., F.B., C.C., K.C., A.R., J.L., G.I., E.P. and N.Y. Development and contribution of reagents: C.R.-P., L.F., E.W., D.L., S.O., L.T., N.P., D.L., L.M., H.W. and A.O. Data analysis: E.G., B.Z., S.D., F.B., K.C., A.R., J.L., G.I., E.P., K.M.R., K.B., J.-E.R. and S.W.G.T. Intellectual input: E.G., N.Y., M.L.A., A.O., J.-E.R., K.B. and S.W.G.T. Manuscript writing: E.G. and S.W.G.T.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stephen W. G. Tait.

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DOI

https://doi.org/10.1038/ncb3596

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