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