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

Giampazolias, E. et al. (2017) Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Nature Cell Biology, 19(9), pp. 1116-1129. (doi:10.1038/ncb3596) (PMID:28846096)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Machesky, Professor Laura and Blyth, Dr Karen and Giampazolias, Mr Evangelos and Ichim, Dr Gabriel and Cloix, Dr Catherine and Milling, Professor Simon and Roca, Alba and Ryan, Professor Kevin and Fort, Loic and Woodham, Emma and Tait, Professor Stephen and Lopez, Dr Jonathan and Cao, Dr Kai
Authors: Giampazolias, E., Zunino, B., Dhayade, S., Bock, F., Cloix, C., Cao, K., Roca, A., Lopez, J., Ichim, G., Proïcs, E., Rubio-Patiño, C., Fort, L., Yatim, N., Woodham, E., Orozco, S., Taraborrelli, L., Peltzer, N., Lecis, D., Machesky, L., Walczak, H., Albert, M. L., Milling, S., Oberst, A., Ricci, J.-E., Ryan, K. M., Blyth, K., and Tait, S. W.G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Cell Biology
Publisher:Nature Publishing Group
ISSN:1465-7392
ISSN (Online):1476-4679
Published Online:28 August 2017
Copyright Holders:Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature
First Published:First published in Nature Cell Biology 19(9):1116-1129
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
690911Apoptosis as an oncogenic process: understanding and exploiting its dark-sideStephen TaitCancer Research UK (CRUK)C40872/A20145RI CANCER SCIENCES
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)C596/A18076RI CANCER SCIENCES