Mitochondrial bioenergetics is associated with aggressive breast cancer growth

尽管转移性乳腺癌仍然是一种不治之症，但对转移性疾病分子生物学的了解日益加深，使得针对特定分子靶点的治疗方法得以发展。阐明辐射抵抗乳腺癌细胞，尤其是肿瘤干细胞的机制，将为确定有效的放射增敏靶点提供重要信息。代替目前认为的有氧糖酵解，我们建议测试一种范式转换的想法，即线粒体生物能量学是侵袭性癌症生长的主要细胞燃料供应，特别是在辐射抵抗的乳腺癌干细胞中。PI实验室的一项里程碑式的工作发现了一小部分 乳腺癌干细胞(BCSCs)在放疗后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+BCSCs的一个独特的代谢特征是在辐射损伤下从以有氧糖酵解为主(Warburg效应)向线粒体主导的生物能量学转变。这种应激诱导的线粒体能量增加重新编程需要CDK1的线粒体重新定位和线粒体内无数关键CDK1靶标的磷酸化(即STAT3、SIRT3、复合体I亚基、MnSOD)。将正常的核细胞周期激酶CDK1转位到线粒体以增强线粒体的生物能量学是线粒体领域的一项开创性工作，对肿瘤新陈代谢具有许多意义。线粒体特异性CDK1缺失的细胞在辐射后存活率降低。这些结果表明，CDK1作用于其线粒体靶点，上调线粒体能量输出，使HER2+BCSCs存活并适应治疗环境，从而导致攻击性和抵抗性行为，这是一种新的代谢机制。核心假设是CDK1的激活增强了线粒体生物能量学，导致HER2+BCSCs的DNA修复能力增强和侵袭性生长；阻断CDK1介导的线粒体生物能量学是使乳腺肿瘤对辐射重新敏感的有效途径。具体目标有三个： 目的1.研究照射后乳腺癌细胞线粒体的生物遗传学特征。目的2.研究CDK1介导的HER2+BCSCs线粒体生物能量学。目的3.通过阻断CDK1介导的线粒体生物能量学来评价HER2+BCSCs的放射增敏作用。这项建议的主要目标是研究CDK1如何调节线粒体生物能量学的重新编程，导致乳腺癌干细胞HER2+BCSCs的辐射抗性。 随后，线粒体CDK1和/或其关键的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点。

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.