Silencing of NAC1 Expression Induces Cancer Cells Oxidative Stress in Hypoxia and Potentiates the Therapeutic Activity of Elesclomol.
Silencing of NAC1 Expression Induces Cancer Cells Oxidative Stress in Hypoxia and Potentiates the Therapeutic Activity of Elesclomol.
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沉默 NAC1 表达会诱导癌细胞在缺氧条件下产生氧化应激，并增强艾司洛莫的治疗活性
DOI：
10.3389/fphar.2017.00804
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发表时间：
2017
影响因子：
5.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Ren YJ;Wang XH;Ji C;Guan YD;Lu XJ;Liu XR;Zhang HH;Guo LC;Xu QH;Zhu WD;Ming ZJ;Yang JM;Cheng Y;Zhang Y
为了在低氧条件下生存，癌细胞可进行代谢转换为糖酵解并抑制线粒体呼吸，以减少氧气消耗并防止过量活性氧（ROS）产生。伏隔核相关蛋白1（NAC1）是BTB/POZ基因家族的一种核蛋白，在癌症发展中起关键作用。在此，我们确定NAC1 - PDK3轴对于抑制线粒体功能、氧气消耗以及更有害的ROS产生是必需的，并在低氧条件下保护癌细胞免于凋亡。我们表明，NAC1通过在转录水平上由缺氧诱导因子 - 1α（HIF - 1α）诱导丙酮酸脱氢酶激酶3（PDK3）的表达来介导低氧条件下线粒体功能的抑制，从而使丙酮酸脱氢酶失活并减弱线粒体呼吸。在缺乏NAC1的细胞中重新表达PDK3可使细胞从低氧诱导的代谢应激中恢复，并在异种移植小鼠模型中恢复糖酵解活性，同时表明沉默NAC1表达可增强 elesclomol（一种促氧化剂）的抗肿瘤功效。我们的研究结果揭示了一种新的机制，即NAC1在癌症进展过程中促进抗氧化应激以及在癌症治疗中产生化疗耐药性。
In order to survive under conditions of low oxygen, cancer cells can undergo a metabolic switch to glycolysis and suppress mitochondrial respiration in order to reduce oxygen consumption and prevent excessive amounts of reactive oxygen species (ROS) production. Nucleus accumbens-1 (NAC1), a nuclear protein of the BTB/POZ gene family, has pivotal roles in cancer development. Here, we identified that NAC1-PDK3 axis as necessary for suppression of mitochondrial function, oxygen consumption, and more harmful ROS generation and protects cancer cells from apoptosis in hypoxia. We show that NAC1 mediates suppression of mitochondrial function in hypoxia through inducing expression of pyruvate dehydrogenase kinase 3 (PDK3) by HIF-1α at the transcriptional level, thereby inactivating pyruvate dehydrogenase and attenuating mitochondrial respiration. Re-expression of PDK3 in NAC1 absent cells rescued cells from hypoxia-induced metabolic stress and restored the activity of glycolysis in a xenograft mouse model, and demonstrated that silencing of NAC1 expression can enhance the antitumor efficacy of elesclomol, a pro-oxidative agent. Our findings reveal a novel mechanism by which NAC1 facilitates oxidative stress resistance during cancer progression, and chemo-resistance in cancer therapy.
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DOI：
10.1097/mco.0b013e32833a5577
发表时间：
2010-07-01
影响因子：
3.1
作者：
Annibaldi, Alessandro;Widmann, Christian
通讯作者：
Widmann, Christian
影响因子：
45.3
作者：
O'Day, Steven;Gonzalez, Rene;Jacobson, Eric
通讯作者：
Jacobson, Eric
影响因子：
4
作者：
Stead MA;Wright SC
通讯作者：
Wright SC
影响因子：
--
作者：
Ueda SM;Yap KL;Davidson B;Tian Y;Murthy V;Wang TL;Visvanathan K;Kuhajda FP;Bristow RE;Zhang H;Shih IeM
通讯作者：
Shih IeM
DOI：
10.1038/modpathol.2010.230
发表时间：
2011-05
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
通讯作者：
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