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.

中文翻译：

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Caspase 缺乏时，线粒体透化会参与 NF-κB 依赖性抗肿瘤活性。


细胞凋亡是一种关键的抗癌治疗效应机制。在细胞凋亡过程中，即使没有 caspase 活性，线粒体外膜透化 (MOMP) 通常也会杀死细胞。 Caspase 活性还会产生多种不良后果，包括 DNA 损伤。因此，我们研究了 MOMP 诱导的不依赖半胱天冬酶的细胞死亡 (CICD) 是否可能是杀死癌细胞的更好方法。我们发现经历 CICD 的细胞表现出与细胞凋亡相关的有效促炎作用。在此基础上，MOMP 通过下调凋亡蛋白抑制剂来刺激 NF-κB 活性。引人注目的是，CICD 的参与显示出有效的抗肿瘤作用，通常以依赖于完整免疫的方式促进肿瘤完全消退。我们的数据表明，通过激活 NF-κB，MOMP 除了触发细胞死亡之外还可以发挥额外的信号传导功能。此外，他们支持在细胞杀伤性抗癌疗法中引入不依赖半胱天冬酶的细胞死亡的基本原理。