Role of SOD1 in cancer

描述（由申请人提供）：癌细胞的特征是代谢重编程，涉及从线粒体呼吸到有氧糖酵解的转换，称为Warburg效应，以及活性氧（ROS）积累导致的氧化应激水平升高。虽然低水平的ROS激活信号级联反应，但过量的ROS会导致细胞死亡。因此，癌细胞需要发展将ROS维持在中等水平的机制。IM中呼吸链的组分在IM两侧产生超氧化物（O2）；无论是在矩阵中还是在IMS中。在基质中，SIRT3调节超氧化物歧化酶SOD2的活性，SOD2将O2转化为过氧化氢（H2O2）。然而，SIRT3的表达在87%的乳腺癌中降低，这种效应对Warburg效应至关重要。我们的研究表明，SOD1表达的增加及其导入IMS对于抵消SIRT3的减少至关重要，从而使癌细胞中的总O2水平保持适度。由于我们发现SOD1的增加是独立于癌基因的，因此SOD1表达的增加可能是癌细胞支持其代谢重编程的普遍管家功能。我们发现SOD1水平受线粒体泛素连接酶Mulan的调节。此外，我们发现IMS中ROS的积累导致Mulan的消除和SOD1的稳定。这些发现表明Mulan在限制SOD1进入IMS方面起着守门人的作用。为了进一步测试SOD1在癌症中的基本管家功能，并解剖Mulan对SOD1的全新调节模式，我们提出以下具体目标：具体目标1：在体内验证SOD1作为治疗靶点。具体目的2：检测花木兰对SOD1的调节作用。具体目的3：氧化应激对花木兰的调节作用。

DESCRIPTION (provided by applicant): Cancer cells are characterized by a metabolic reprogramming involving a switch from mitochondrial respiration to aerobic glycolysis, known as the Warburg effect and by an elevated level of oxidative stress as a result of the accumulation of reactive oxygen species (ROS). While low levels of ROS activate signaling cascades, excessive levels of ROS cause cell death. Therefore, cancer cells need to develop mechanisms to maintain ROS at moderate levels. Components of the respiratory chain in the IM generate superoxide (O2) on both sides the IM; both in the matrix and in the IMS. In the matrix, SIRT3 regulates the activity of the superoxide dismutase SOD2, which converts O2 into hydrogen peroxide (H2O2). However, the expression of SIRT3 is reduced in 87% of breast cancers and this effect is essential for the Warburg effect. Our work shows that increased expression of SOD1 and its import into the IMS is essential to counterbalance the decrease in SIRT3 so that the total levels of O2 in cancer cells remain moderate. Since we found that the increase in SOD1 is independent of oncogene, increased expression of SOD1 maybe a universal housekeeping function of cancer cells to support their metabolic reprogramming. We show that SOD1 levels are regulated by the mitochondria ubiquitin ligase Mulan. Further, we found that accumulation of ROS in the IMS leads to the elimination of Mulan and the stabilization of SOD1. These findings suggest that Mulan acts as a gatekeeper to limit the entry of SOD1 into the IMS. To further test the essential housekeeping function of SOD1 in cancer and to dissect this entirely new mode of regulation of SOD1 by Mulan, we propose the following specific aims: Specific aim 1: In vivo validation of SOD1 as a target for therapy. Specific aim 2: Testing the regulation of SOD1 by Mulan. Specific aim 3: Regulation of Mulan by oxidative stress.