Metabolic Control and Anticancer Mechanism

摘要 mTORC 1通路作为肿瘤生长和代谢的中心控制器，通常被突变和激活 在人类癌症中，导致不受控制的生长。癌细胞对升高的mTORC 1信号传导“上瘾”， 使得mTORC 1成为理想的癌症药物靶标。高度特异性mTORC 1抑制剂雷帕霉素类似物 （雷帕霉素类似物，例如替西罗莫司）是美国FDA批准的肿瘤药物。然而，他们的临床反应一直是 中度，这在很大程度上是由于对mTORC1信号传导机制的不完全理解 支持雷帕霉素的作用。在本申请中，我们将检验核心假设，即核mTORC 1 信号通过长的非编码RNA（lncRNA）NEAT 1促进有氧糖酵解，或瓦尔堡效应。 依赖性机制，这对mTORC 1驱动的肿瘤发生和雷帕霉素反应很重要。一 该项目的成功完成将提供对这一致癌途径的更深入了解， 治疗反应。

ABSTRACT As a central controller of cancer growth and metabolism, mTORC1 pathway is commonly mutated and activated in human cancer, leading to uncontrolled growth. Cancer cells are ‘addicted’ to elevated mTORC1 signaling, rendering mTORC1 a desirable cancer drug target. The highly specific mTORC1 inhibitors rapamycin analogs (rapalogs, e.g. temsirolimus) are US FDA-approved oncology drugs. However, their clinical response has been moderate, which is in a large part due to incomplete understanding of mTORC1 signaling mechanisms underpinning rapamycin action. In this application, we will test the central hypothesis that nuclear mTORC1 signaling promotes aerobic glycolysis, or Warburg Effect, through a long non-coding RNA (lncRNA) NEAT1- dependent mechanism, which is important for mTORC1-driven tumorigenesis and rapamycin response. A successful completion of this project will provide a deeper understanding of this oncogenic pathway and therapeutic response to its blockage.