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