TFAM is a novel mediator of immunogenic cancer cell death.
TFAM is a novel mediator of immunogenic cancer cell death.
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TFAM 是免疫原性癌细胞死亡的新型介质
DOI：
10.1080/2162402x.2018.1431086
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Kang R
中科院分区：
文献类型：
--
作者：
Yang M;Li C;Zhu S;Cao L;Kroemer G;Zeh H;Tang D;Kang R
免疫原性细胞死亡（ICD）是一种伴随着损伤相关分子模式（DAMP）释放并导致死细胞抗原特异性免疫应答的细胞死亡。在这里，我们报告spautin-1，一种泛素特异性肽酶的抑制剂，在体外和体内触发免疫原性癌细胞死亡。spautin-1的抗癌活性不依赖于自噬抑制，但依赖于内在的线粒体凋亡途径。SpaA-1导致线粒体氧化损伤，这导致JUN转录因子以JNK依赖性方式激活。从机制上讲，spautin-1激活JUN通过上调促凋亡BAD表达导致凋亡。重要的是，凋亡细胞释放TFAM（一种线粒体DAMP）可能通过其对受体AGER的作用促进spautin-1诱导的ICD。事实上，在体外用spautin-1处理的癌细胞在体内接种时，在不存在任何佐剂的情况下能够引发抗癌免疫应答。当TFAM或AGER被特异性抗体中和时，spautin-1处理的癌细胞的这种免疫原性作用丧失。总之，我们的研究结果表明，spautin-1可能会刺激导致ICD的凋亡途径，在TFAM和AGER依赖的方式。
ABSTRACT Immunogenic cell death (ICD) is a type of cell death that is accompanied by the release of damage-associated molecular patterns (DAMPs) and results in a dead-cell antigen-specific immune response. Here, we report that spautin-1, an inhibitor of ubiquitin-specific peptidases, triggers immunogenic cancer cell death in vitro and in vivo. The anticancer activity of spautin-1 occurs independent of autophagy inhibition, but depends on the intrinsic mitochondrial apoptosis pathway. Spautin-1 causes mitochondrial oxidative injury, which results in JUN transcription factor activation in a JNK-dependent manner. Mechanistically, activation of JUN by spautin-1 leads to apoptosis by upregulation of pro-apoptotic BAD expression. Importantly, the release of TFAM, a mitochondrial DAMP, by apoptotic cells may contribute to spautin-1-induced ICD via its action on the receptor AGER. Indeed, cancer cells treated with spautin-1 in vitro were able to elicit an anticancer immune response when inoculated in vivo, in the absence of any adjuvant. This immunogenic effect of spautin-1-treated cancer cells was lost when TFAM or AGER were neutralized by specific antibodies. Altogether, our results suggest that spautin-1 may stimulate an apoptotic pathway that results in ICD, in TFAM- and AGER-dependent fashion.