Mitochondrial bioenergetics is associated with aggressive breast cancer growth

线粒体生物能学与侵袭性乳腺癌生长相关

基本信息

批准号：
10082438
负责人：
Jian Jian Li
金额：
$ 35.91万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082438
关键词：
Adenosine Triphosphate Anabolism Automobile Driving Behavior Bioenergetics Breast Cancer Cell CDC2 gene Cell Cycle Cell Cycle Progression Cell Proliferation Cell Survival Cell Therapy Cells Chemoresistance Clinical Complex DNA Repair Data Disease Dose ERBB2 gene Generations Genotoxic Stress Glycolysis Goals Growth Homeostasis Ionizing radiation Irradiated tumor Link Literature M cell Malignant Neoplasms Mammary Neoplasms Mediating Metabolic Metastatic breast cancer Metastatic/Recurrent Mitochondria Molecular Biology Molecular Target Neoplasm Metastasis Nuclear Output Phenotype Phosphorylation Phosphotransferases Radiation Radiation therapy Radiosensitization Reporting Resistance Respiration SOD2 gene STAT3 gene Source Stress Testing Therapeutic Trastuzumab Tumor Cell Invasion Warburg Effect Work aerobic glycolysis aggressive breast cancer cancer radiation therapy cancer stem cell cancer therapy cell growth comparative cyclin B1 efficacy evaluation in vivo insight malignant breast neoplasm mutant neoplastic cell radiation resistance radioresistant response stemness therapeutic target therapeutically effective therapy development trafficking tumor tumor metabolism tumor xenograft

项目摘要

Although metastatic breast cancer is still an incurable disease, the increasing understanding of the molecular biology of metastatic disease has allowed the development of therapies aimed at specific molecular targets. To elucidate the mechanistic insights of radioresistant breast cancer cells especially the cancer stem cells will provide important information to define effective radiosensitization targets. Instead of the currently believed aerobic glycolysis, we propose to test a paradigm shifting idea that mitochondrial bioenergetics is the major cellular fuel supply for aggressive cancer growth, especially in the radioresistant breast cancer stem cells. A milestone work from the PI's lab identified a fraction of breast cancer stem cells (BCSCs) expressing HER2 (HER2+ BCSCs) in the radiation-surviving breast cancer cells and in the recurrent/metastatic breast tumors. A unique metabolic feature of HER2+ BCSCs is characterized by a shift from the aerobic glycolysis dominant (Warburg effect) to the mitochondrial governed bioenergetics under radiation insult. Such stress-induced reprogramming of mitochondrial energy boost requires the mitochondrial relocation of CDK1 and phosphorylation of a myriad of critical CDK1 targets inside the mitochondria (i.e., STAT3, SIRT3, complex I subunits, MnSOD). Translocation of normally nuclear cell cycle kinase CDK1 into the mitochondria for enhancing the mitochondrial bioenergetics is a pioneer work in the field of mitochondria and has many implications for tumor metabolism. Cells harboring deficient mitochondria-specific CDK1 showed reduced survival after radiation. These results indicate a new metabolic mechanism by which CDK1 acting upon its mitochondrial targets up-regulates mitochondrial energy output for HER2+ BCSCs to survive and adapt to the therapeutic circumstances, causing aggressive and resistant behavior. The central hypothesis is that activation of CDK1 enhances mitochondrial bioenergetics, leading to the increased capacity of DNA repair and aggressive growth of HER2+ BCSCs; blocking CDK1-mediated mitochondrial bioenergetics is an effective approach to re-sensitize breast tumors to radiation. There are Three Specific Aims: Aim 1. Characterize mitochondrial biogenetics in irradiated breast cancer cells. Aim 2. Investigate CDK1-mediated mitochondrial bioenergetics in HER2+ BCSCs. Aim 3. Evaluate radiosensitization of HER2+ BCSCs by blocking CDK1-mediated mitochondrial bioenergetics. The overarching goals of this proposal are to study how CDK1 regulates the reprogramming of mitochondrial bioenergetics causing radioresistance of breast cancer stem cells HER2+ BCSCs. Subsequently, the mitochondrial CDK1 and/or its key mitochondria substrates will be identified as aspecific molecular target for radiosensitization of resistant breast cancer.

尽管转移性乳腺癌仍然是一种无法治愈的疾病，但对转移性疾病分子生物学的日益了解使得针对特定分子靶点的疗法得以开发。为了阐明放射抗性乳腺癌细胞尤其是癌症干细胞的机制见解，将为定义有效的放射增敏靶点提供重要信息。我们建议测试一种范式转变的想法，而不是目前认为的有氧糖酵解，即线粒体生物能是侵袭性癌症生长的主要细胞燃料供应，特别是在抗辐射乳腺癌干细胞中。 PI 实验室的一项里程碑式工作确定了一小部分乳腺癌干细胞 (BCSC) 在辐射存活的乳腺癌细胞和复发/转移性乳腺肿瘤中表达 HER2 (HER2+ BCSC)。 HER2+ BCSC 的一个独特的代谢特征是在辐射损伤下从有氧糖酵解主导（瓦尔堡效应）转变为线粒体控制的生物能学。这种应激诱导的线粒体能量增强重编程需要 CDK1 在线粒体中的重新定位以及线粒体内无数关键 CDK1 靶标（即 STAT3、SIRT3、复合物 I 亚基、MnSOD）的磷酸化。将正常核细胞周期激酶 CDK1 转入线粒体以增强线粒体生物能学是线粒体领域的开创性工作，对肿瘤代谢具有许多影响。含有缺陷的线粒体特异性 CDK1 的细胞在辐射后表现出存活率降低。这些结果表明了一种新的代谢机制，通过该机制，CDK1 作用于其线粒体靶标，上调线粒体能量输出，使 HER2+ BCSC 能够生存并适应治疗环境，从而引起攻击性和抵抗行为。中心假设是 CDK1 的激活增强线粒体生物能，导致 DNA 修复能力增强和 HER2+ BCSC 的快速生长；阻断 CDK1 介导的线粒体生物能学是使乳腺肿瘤对放射重新敏感的有效方法。有三个具体目标：目标 1. 表征受辐射乳腺癌细胞的线粒体生物遗传学。目标 2. 研究 HER2+ BCSC 中 CDK1 介导的线粒体生物能学。目标 3. 通过阻断 CDK1 介导的线粒体生物能来评估 HER2+ BCSC 的放射增敏作用。该提案的总体目标是研究 CDK1 如何调节线粒体生物能量的重编程，从而导致乳腺癌干细胞 HER2+ BCSC 的放射抗性。随后，线粒体 CDK1 和/或其关键线粒体底物将被确定为耐药乳腺癌放射增敏的特异性分子靶标。