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

Evangelos Giampazolias, Barbara Zunino, Sandeep Dhayade, Florian Bock, Catherine Cloix, Kai Cao, Alba Roca, Jonathan Lopez, Gabriel Ichim, Emma Proïcs, Camila Rubio-Patiño, Loic Fort, Nader Yatim, Emma Woodham, Susana Orozco, Lucia Taraborrelli, Nieves Peltzer, Daniele Lecis, Laura Machesky, Henning WalczakMatthew L. Albert, Simon Milling, Andrew Oberst, Jean Ehrland Ricci, Kevin M. Ryan, Karen Blyth, Stephen W.G. Tait

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1116-1129
Number of pages14
JournalNature Cell Biology
Volume19
Issue number9
DOIs
Publication statusPublished - Sep 1 2017

ASJC Scopus subject areas

  • Cell Biology

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    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., ... Tait, S. W. G. (2017). Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Nature Cell Biology, 19(9), 1116-1129. https://doi.org/10.1038/ncb3596