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

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

来源：Nature Cell Biology, 2017, 19(9): 1116-+.

DOI：10.1038/ncb3596

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-kappa B 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-kappa B, 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.

• 出版日期2017-9