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Mitochondrial permeabilization engages NF-kappa B-dependent anti-tumour activity under caspase deficiency

Giampazolias, E; Zunino, B; Dhayade, S; Bock, F; Cloix, C; Cao, K; Roca, A; ... Tait, SWG; + view all (2017) Mitochondrial permeabilization engages NF-kappa B-dependent anti-tumour activity under caspase deficiency. Nature Cell Biology , 19 (9) pp. 1116-1129. 10.1038/ncb3596. Green open access

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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.

Type: Article
Title: Mitochondrial permeabilization engages NF-kappa B-dependent anti-tumour activity under caspase deficiency
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ncb3596
Publisher version: http://doi.org/10.1038/ncb3596
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, CELL-DEATH, TNF-ALPHA, INDUCED APOPTOSIS, CANCER, ACTIVATION, INSTABILITY, INHIBITOR, PATHWAY, KINASE, RIPK1
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/10047090
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