脯氨酸羟化酶EglN1转位到线粒体介导乳腺癌细胞适应缺氧应激的机制研究

目前乳腺癌是全球第一大癌，其多数患者在治疗中显示出耐药。研究表明，线粒体代谢与乳腺癌耐药紧密相关，提示靶向线粒体代谢通路有望解决临床治疗耐药难题。肿瘤缺氧是临床治疗耐药的重要因素，缺氧致使线粒体代谢重编辑，但其中的分子机制尚不清楚。我们的前期工作中发现缺氧诱导经典氧气感受体EglN1转移至线粒体，通过协同调控AMPK和mTOR信号通路调节线粒体代谢，满足分解代谢和合成代谢供求平衡，以确保肿瘤细胞在缺氧环境中的生存与增殖。本项目将在分子机制方面进一步深入研究EglN1在缺氧条件下如何转位到线粒体以及如何协同调控AMPK和mTOR信号通路进而调节线粒体代谢以促进肿瘤的发生发展。该项目的成功完成将揭示经典氧气感受体EglN1应答缺氧调控重要代谢信号通路AMPK和mTOR进而影响线粒体功能的新机制，完善经典氧气感受信号通路与代谢的交互调节机制，也将为肿瘤治疗提供新的理论依据和新的分子靶标。

Breast cancer is the leading cause of cancer death among women. According to the latest data from WHO's International Agency for Research on Cancer (IARC), breast cancer has been the first common cancer in the world with more than 2 million of new cases during 2020. Approximately 75% of breast cancer is estrogen receptor positive (ER+), and anti-estrogen therapy has been proved to be highly effective in treatment of ER+ breast cancer. However, up to 50% of patients have primary or acquired resistance, highlight the urgent need of effective targeted agent. Various studies have shown that mitochondrial metabolism play a central role in breast cancer endocrine resistance, which means mitochondrial metabolism is a potential target for breast cancer treatment. Hypoxia is the main cause of drug resistant in tumor cells and mitochondrial metabolism is reprogrammed under hypoxia, but the mechanism remains ambiguous. In our preliminary studies, we found that EglN1 transfers to mitochondria under hypoxia. We have discovered that EglN1 regulates mitochondrial metabolism through coordinately regulating AMPK signaling pathway and mTOR signaling pathway, thereby balancing the catabolism and anabolism, so as to maintain the survival and proliferation of tumor cells under hypoxia. This project will further investigate the mechanism of how EglN1 transfers to mitochondria. In addition, it will further exam the molecular mechanisms of how EglN1 regulates the function of AMPK and mTOR to adjust the mitochondrial metabolism, so as to maintain the survival and proliferation of tumor cells under hypoxia. These studies will not only reveal an important mechanism of how the classical oxygen sensor EglN1 regulates mitochondrial metabolism through regulating AMPK and mTOR signaling pathways under hypoxia, improving or understanding of the intersection between oxygen sensing pathway and cell metabolism, but also set the stage for development of novel anti-cancer approaches.