Deletion of Pim kinases elevates the cellular levels of reactive oxygen species and sensitizes to K-Ras-induced cell killing.
Deletion of Pim kinases elevates the cellular levels of reactive oxygen species and sensitizes to K-Ras-induced cell killing.
复制标题
作者：
Pim蛋白激酶通过增强致癌Myc和Ras的活性而促进转化，这在肿瘤发生期间驱动显著的代谢变化。在这份报告中，我们证明，小鼠胚胎成纤维细胞（MEFs）缺乏所有三种亚型的Pim蛋白激酶，三重敲除（TKO），不能容忍活化的K-Ras（K-RasG 12 V）的表达，并进行细胞死亡。K-RasG 12 V转导入这些细胞显著增加了细胞活性氧（ROS）的水平。N-乙酰半胱氨酸的加入减弱了ROS的产生，并逆转了K-RasG 12 V在TKO MEFs中的细胞毒性作用。由于糖酵解和戊糖磷酸途径中代谢中间体水平降低以及线粒体氧化磷酸化异常，导致Pim丢失导致细胞氧化还原状态改变。TKO MEF表现出降低的超氧化物歧化酶（Sod）、谷胱甘肽过氧化物酶4（Gpx 4）和过氧化物氧还蛋白3（Prdx 3）水平，这使得它们对K-RasG 12 V介导的ROS产生的杀伤敏感。相反，将c-Myc转导到TKO细胞中可以通过调节细胞代谢和Sod 2来克服Pim蛋白激酶的缺乏。在不存在Pim激酶的情况下，c-Myc转导通过降低Ras诱导的细胞ROS水平而允许K-RasG 12 V诱导的细胞生长。这些结果表明Pim蛋白激酶在调节细胞氧化还原、代谢和K-Ras刺激的细胞生长中起重要作用。
The Pim protein kinases contribute to transformation by enhancing the activity of oncogenic Myc and Ras, which drives significant metabolic changes during tumorigenesis. In this report, we demonstrate that mouse embryo fibroblasts (MEFs) lacking all three isoforms of Pim protein kinases, triple knockout (TKO), cannot tolerate the expression of activated K-Ras (K-RasG12V) and undergo cell death. Transduction of K-RasG12V into these cells markedly increased the level of cellular reactive oxygen species (ROS). The addition of N-acetyl cysteine attenuates ROS production and reversed the cytotoxic effects of K-RasG12V in the TKO MEFs. The altered cellular redox state caused by the loss of Pim occurred as a result of lower levels of metabolic intermediates in the glycolytic and pentose phosphate pathways as well as abnormal mitochondrial oxidative phosphorylation. TKO MEFs exhibit reduced levels of superoxide dismutase (Sod), glutathione peroxidase 4 (Gpx4) and peroxiredoxin 3 (Prdx3) that render them susceptible to killing by K-RasG12V-mediated ROS production. In contrast, the transduction of c-Myc into TKO cells can overcome the lack of Pim protein kinases by regulating cellular metabolism and Sod2. In the absence of the Pim kinases, c-Myc transduction permitted K-RasG12V-induced cell growth by decreasing Ras-induced cellular ROS levels. These results demonstrate that the Pim protein kinases play an important role in regulating cellular redox, metabolism and K-Ras-stimulated cell growth.
登录
查看更多内容
影响因子：
11.2
作者：
Cai H;Memarzadeh S;Stoyanova T;Beharry Z;Kraft AS;Witte ON
通讯作者：
Witte ON
DOI：
10.1126/science.1243417
发表时间：
2013-11-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Peek CB;Affinati AH;Ramsey KM;Kuo HY;Yu W;Sena LA;Ilkayeva O;Marcheva B;Kobayashi Y;Omura C;Levine DC;Bacsik DJ;Gius D;Newgard CB;Goetzman E;Chandel NS;Denu JM;Mrksich M;Bass J
通讯作者：
Bass J
影响因子：
9.9
作者：
Gaglio, Daniela;Metallo, Christian M.;Chiaradonna, Ferdinando
通讯作者：
Chiaradonna, Ferdinando
影响因子：
20.3
作者：
Lu, Jing;Zavorotinskaya, Tatiana;Garcia, Pablo D.
通讯作者：
Garcia, Pablo D.
影响因子：
4.8
作者：
Osthus, RC;Shim, H;Dang, CV
通讯作者：
Dang, CV