Mitohormesis Primes Tumor Invasion and Metastasis
Mitohormesis Primes Tumor Invasion and Metastasis
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DOI：
10.1016/j.celrep.2019.04.095
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发表时间：
2019-05-21
期刊：
影响因子：
8.8
通讯作者：
Germain, Doris
中科院分区：
文献类型：
--
作者：
Kenny, Timothy C.;Craig, Amanda J.;Germain, Doris
中度线粒体应激可导致细胞保护机制的持续激活-一种称为有丝分裂的现象。在这里，我们表明，有丝分裂引发癌细胞的亚群基本上调线粒体应激反应，如线粒体未折叠蛋白反应（UPRmt）提供了适应性转移优势。在该亚群中，UPRmt活化在没有应激的情况下持续存在，导致指示有丝分裂的氧化应激降低。从机制上讲，我们发现UPRmt的SIRT 3轴是侵袭和转移所必需的。在乳腺癌患者中，7个基因的UPRmt特征表明，UPRmt-HIGH患者的临床结局显著更差，包括转移。转录组学分析显示，UPRmt-HIGH患者具有以转移程序和有丝分裂的细胞保护结果为特征的表达谱。虽然在非病理环境中，有丝分裂与健康和长寿有关，但这些结果表明，癌细胞有害地利用它来促进肿瘤进展。
Moderate mitochondrial stress can lead to persistent activation of cytoprotective mechanisms - a phenomenon termed mitohormesis. Here, we show that mitohormesis primes a subpopulation of cancer cells to basally upregulate mitochondrial stress responses, such as the mitochondrial unfolded protein response (UPRmt) providing an adaptive metastatic advantage. In this subpopulation, UPRmt activation persists in the absence of stress, resulting in reduced oxidative stress indicative of mitohormesis. Mechanistically, we showed that the SIRT3 axis of UPRmt is necessary for invasion and metastasis. In breast cancer patients, a 7-gene UPRmt signature demonstrated that UPRmt-HIGH patients have significantly worse clinical outcomes, including metastasis. Transcriptomic analyses revealed that UPRmt-HIGH patients have expression profiles characterized by metastatic programs and the cytoprotective outcomes of mitohormesis. While mitohormesis is associated with health and longevity in non-pathological settings, these results indicate that it is perniciously used by cancer cells to promote tumor progression.