Role of SOD1 in cancer

描述(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，以及由于活性氧物种(ROS)的积累而导致的氧化应激水平升高。虽然低水平的ROS激活了信号级联，但过高的ROS水平会导致细胞死亡。因此，癌细胞需要发展机制来维持适度的ROS水平。IM中呼吸链的成分在IM两侧产生超氧化物(O2)；在基质和IM中都是如此。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在87%的乳腺癌中表达降低，这一效应对于Warburg效应是必不可少的。我们的工作表明，增加SOD1的表达并将其导入IMS对于抵消SIRT3的减少至关重要，从而使癌细胞中的O2总水平保持适度。由于我们发现SOD1的增加不依赖于癌基因，SOD1的表达增加可能是癌细胞的一种普遍的管家功能，以支持其代谢重新编程。我们发现SOD1的水平受线粒体泛素连接酶木兰的调节。此外，我们还发现，ROS在IMS中的积累导致了木兰的消除和SOD1的稳定。这些发现表明，花木兰扮演了一个把关人的角色，限制SOD1进入IMS。为了进一步测试SOD1在癌症中的基本管家功能，并剖析木兰调控SOD1的这一全新模式，我们提出了以下特定目标：特定目标1：体内验证SOD1作为治疗靶点。具体目标2：检测花木兰对SOD1的调节作用。具体目标3：氧化应激对花木兰的调节。

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.