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Nat Cell Biol. 2017 Sep;19(9):1116-1129. doi: 10.1038/ncb3596. Epub 2017 Aug 28.

Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency.

Author information

1
Cancer Research UK Beatson Institute, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
2
Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
3
Université Côte d'Azur, Inserm, C3M, France.
4
Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France.
5
Molecular &Cellular Biology Program and Department of Immunology, University of Washington, 750 Republican Street, Seattle, Washington 98109, USA.
6
Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, UCL, London WC1E 6BT, UK.
7
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy.
8
Department of Cancer Immunology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
9
Centre for Immunobiology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.

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.

PMID:
28846096
PMCID:
PMC5624512
DOI:
10.1038/ncb3596
[Indexed for MEDLINE]
Free PMC Article

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