Metabolic Control and Anticancer Mechanism

代谢控制与抗癌机制

• 批准号: 10661493
• 负责人: STEVEN ZHENG
• 金额: $ 33.43万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661493
• 关键词: Antineoplastic Agents; Biogenesis; CCI-779; Clinical; Data; Drug Targeting; Event; FDA approved; Genes; Genetic Transcription; Growth; Human; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolism; Mutate; Nuclear; Nutrient; Oncogenic; Oncology; Oxidative Phosphorylation; Oxygen; Pathway interactions; Pharmaceutical Preparations; Polymers; Process; RNA Splicing; RNA-Binding Proteins; Regulation; Repression; Signal Transduction; Sirolimus; Stimulus; Structure; Testing; Untranslated RNA; Warburg Effect; aerobic glycolysis; anti-cancer; cancer cell; cell growth; improved outcome; inhibitor; insight; mRNA Precursor; polymerization; response; targeted treatment; treatment response; tumor metabolism; tumorigenesis; tumorigenic

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.

抽象的 作为癌症生长和代谢的中央控制器，MTORC1途径通常被突变并激活 在人类癌症中，导致不受控制的生长。癌细胞“上瘾” MTORC1信号传导， 渲染MTORC1是理想的癌症药物靶标。高度特异的MTORC1抑制剂雷帕霉素类似物 （例如，Temsirolimus）是美国FDA批准的肿瘤药物。但是，他们的临床反应是 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 基础雷帕霉素动作。在此应用中，我们将测试核MTORC1的中心假设 信号传导通过长的非编码RNA（lncRNA）Neat1-促进有氧糖酵解或Warburg效应 依赖机制，这对于MTORC1驱动的肿瘤发生和雷帕霉素反应很重要。一个 成功完成该项目将对这种致癌途径有更深入的了解 对其阻塞的治疗反应。

项目成果

Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis.

mTORC1 磷酸化雄激素受体可促进肝脏脂肪变性和肿瘤发生。

• DOI: 10.1002/hep.32120
• 发表时间: 2022-05
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Ren, Qian-Nan;Zhang, Hong;Sun, Chao-Yue;Zhou, Yu-Feng;Yang, Xue-Feng;Long, Jian-Wu;Li, Xiao-Xing;Mai, Shi-Juan;Zhang, Mei-Yin;Zhang, Hui-Zhong;Mai, Hai-Qiang;Chen, Min-Shan;Zheng, X. F. Steven;Wang, Hui-Yun
• 通讯作者: Wang, Hui-Yun