Role of SOD1 in cancer

SOD1 在癌症中的作用

• 批准号: 8576476
• 负责人: DORIS A GERMAIN
• 金额: $ 35.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8576476
• 关键词: Agreement; Antioxidants; Ants; Apoptosis; Automobile Driving; Cell Death; Cells; Cytoplasm; Data; Deacetylase; Diffuse; Dimerization; Drug Metabolic Detoxication; Energy-Generating Resources; Failure; Gatekeeping; Genetic; Growth; Health; Housekeeping; Human; Human Cell Line; Hydrogen Peroxide; Image; In Vitro; Injection of therapeutic agent; Knockout Mice; Life; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane; Metabolic; Mitochondria; Modeling; Molecular; Monitor; Mouse Mammary Tumor Virus; Oncogenes; Organelles; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Point Mutation; Proteins; Reactive Oxygen Species; Regulation; Respiration; Respiratory Chain; Role; SOD1 gene; SOD2 gene; Side; Signal Transduction; Small Interfering RNA; Stress; Subfamily lentivirinae; Superoxide Dismutase; Superoxides; Testing; Ubiquitination; Validation; Warburg Effect; Work; aerobic glycolysis; cancer cell; in vivo; inhibitor/antagonist; malignant breast neoplasm; mouse model; novel; overexpression; response; tumor; tumor growth; ubiquitin ligase

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.

描述（由申请人提供）：癌细胞的特征是代谢重编程，涉及从线粒体呼吸转变为有氧糖酵解（称为瓦伯格效应），并且由于活性氧（ROS）的积累而导致氧化应激水平升高。低水平的 ROS 会激活信号级联反应，而过量的 ROS 则会导致细胞死亡。因此，癌细胞需要开发机制将 ROS 维持在中等水平。 IM 中呼吸链的组成部分在 IM 两侧产生超氧化物 (O2)；在矩阵和 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，87% 的乳腺癌中 SIRT3 的表达降低，这种效应对于 Warburg 效应至关重要。我们的工作表明，SOD1 表达的增加及其向 IMS 的输入对于平衡 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 的增加与癌基因无关，因此 SOD1 表达的增加可能是癌细胞的普遍管家功能，以支持其代谢重编程。我们发现 SOD1 水平受到线粒体泛素连接酶 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。这些发现表明木兰充当了限制 SOD1 进入 IMS 的看门人。为了进一步测试 SOD1 在癌症中的基本管家功能，并剖析木兰这种全新的 SOD1 调节模式，我们提出以下具体目标： 具体目标 1：体内验证 SOD1 作为治疗靶点。具体目标2：测试木兰对SOD1的调节。具体目标3：氧化应激对木兰的调节。