Fhit-Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells
Fhit-Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells
复制标题
线粒体中脆性组氨酸三联体蛋白（Fhit）与铁氧还蛋白还原酶（Fdxr）的相互作用：对癌细胞中活性氧生成及细胞凋亡的调控
DOI：
10.1038/s41419-019-1414-7
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发表时间：
2019-02-15
影响因子：
9
通讯作者：
Croce, Carlo M.
中科院分区：
文献类型：
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作者：
Druck, Teresa;Cheung, Douglas G.;Croce, Carlo M.
脆性组氨酸三联体（FHIT）蛋白在大多数（或许是所有）癌症类型中缺失；体外实验及小鼠体内肿瘤模型研究表明，当该蛋白恢复表达时，可诱导细胞凋亡并抑制肿瘤形成能力。通过蛋白质交联及蛋白质组学分析，我们对一种参与触发FHIT介导的细胞凋亡的FHIT蛋白复合物进行了表征。该复合物包含热休克伴侣蛋白对HSP60/10，其可能参与将FHIT转运至线粒体，在线粒体中，FHIT与铁氧还蛋白还原酶相互作用，后者负责在电子传递链复合物III中通过铁氧还蛋白将电子从NADPH转移至细胞色素P450。在FHIT缺失的癌细胞中过表达FHIT蛋白可调节细胞内活性氧（ROS）的生成，在过氧化物处理后导致ROS增加，进而使处于氧化应激条件下的肺癌细胞凋亡增多；相反，FHIT阴性细胞可避免ROS过度生成及ROS诱导的细胞凋亡，但其可能携带氧化损伤。因此，对与FHIT相互作用的蛋白质进行表征，已确定了在许多癌症中缺失的FHIT介导的细胞凋亡信号通路的直接效应因子。鉴于近期一些备受瞩目的出版物着重强调氧化磷酸化在人类癌症（尤其是依赖氧化磷酸化维持生存的癌症干细胞）治疗中的作用，这一发现具有转化医学意义。此外，我们已证实，来自FHIT缺失的肺癌细胞系的细胞，在暴露于阿托伐醌时易被杀死，阿托伐醌被认为是一种选择性氧化磷酸化抑制剂，其作用靶点为线粒体复合物III对辅酶Q10的依赖性，而表达FHIT的姐妹克隆细胞对这种处理具有抗性。
Fhit protein is lost in cancers of most, perhaps all, cancer types; when restored, it can induce apoptosis and suppress tumorigenicity, as shown in vitro and in mouse tumor models in vivo. Following protein cross-linking and proteomics analyses, we characterized a Fhit protein complex involved in triggering Fhit-mediated apoptosis. The complex includes the heat-shock chaperonin pair, HSP60/10, which is likely involved in importing Fhit into the mitochondria, where it interacts with ferredoxin reductase, responsible for transferring electrons from NADPH to cytochrome P450 via ferredoxin, in electron transport chain complex III. Overexpression of Fhit protein in Fhit-deficient cancer cells modulates the production of intracellular reactive oxygen species, causing increased ROS, following peroxide treatment, with subsequent increased apoptosis of lung cancer cells under oxidative stress conditions; conversely, Fhit-negative cells escape ROS overproduction and ROS-induced apoptosis, likely carrying oxidative damage. Thus, characterization of Fhit-interacting proteins has identified direct effectors of a Fhit-mediated apoptotic signal pathway that is lost in many cancers. This is of translational interest considering the very recent emphasis in a number of high-profile publications, concerning the role of oxidative phosphorylation in the treatment of human cancers, and especially cancer stem cells that rely upon oxidative phosphorylation for survival. Additionally, we have shown that cells from a Fhit-deficient lung cancer cell line, are sensitive to killing by exposure to atovaquone, thought to act as a selective oxidative phosphorylation inhibitor by targeting the CoQ10 dependence of the mitochondrial complex III, while the Fhit-expressing sister clone is resistant to this treatment.