mTOR Signaling in Tumor Cell Motility

肿瘤细胞运动中的 mTOR 信号转导

• 批准号: 7465549
• 负责人: Shile Huang
• 金额: $ 20.2万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-08 至 2010-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7465549
• 关键词: ANXA5 gene; Adverse effects; Antineoplastic Agents; Biochemical; Bos taurus; Breast; CCI-779; Cattle; Cell Proliferation; Cell Proliferation Regulation; Cells; Cervical Adenocarcinoma; Clinical Trials; Colon; Data; Development; Differentiation and Growth; Focal Adhesion Kinase 1; Focal Adhesions; Genetic; Genus Cola; Goals; Growth; Hela Cells; Human; Insulin-Like Growth Factor I; Kidney; Lead; Malignant neoplasm of brain; Malignant neoplasm of prostate; Mediating; Molecular; Neoplasm Metastasis; Neuroblastoma; Normal Cell; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Predisposition; Prevention; Prostate; Protein Serine/Threonine Phosphatase; Protein phosphatase; Protein-Serine-Threonine Kinases; Proteins; Rhabdomyosarcoma; Role; Serum; Signal Pathway; Signal Transduction; Sirolimus; Solid Neoplasm; Somatomedins; Therapeutic Agents; Tumor Cell Line; Work; annexin A5; cell motility; design; fetal; human BCAR1 protein; inhibitor/antagonist; insight; malignant breast neoplasm; neoplastic cell; novel; paxillin; prevent; protein phosphatase 6; tissue-factor-pathway inhibitor 2; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) controls cell proliferation, growth, differentiation, motility and survival. Transformed or tumor cells with dysregulated mTOR signaling have shown higher susceptibility to inhibitors of mTOR than normal cells, suggesting mTOR inhibitors as potential tumor-selective therapeutic agents. Clinical trials have demonstrated that rapamycin and its derivatives, CCI-779, RAD001 and AP23573 (designated rapamycins) are promising anticancer drugs. They specifically block the function of mTOR, inhibiting growth of types of solid tumors with only mild side effects in patients. However, the anticancer mechanism of rapamycins remains obscure. While intense studies have focused on the role of mTOR in controlling cell proliferation and growth, little is known about how mTOR regulates cell motility. Preliminary studies show that rapamycin inhibits insulin-like growth factor-l (IGF-I) or 10% fetal bovine serum-stimulated motility of a panel of tumor cell lines in culture, suggesting a pivotal role of mTOR not only in cell proliferation but also in cell motility. The long-term goal of the applicant is to understand the molecular mechanism of IGF-l-mTOR signaling in tumorigenesis and metastasis, providing data for development of tumor-selective therapy. Because dysregulation of IGF-l-mTOR signaling pathway occurs frequently in human tumors, the proposed studies will focus on elucidating how mTOR regulates IGF-l-induced cell motility. With a combination of biochemical, molecular, cellular and genetic approaches, the specific aims of this proposal are to determine: (1) whether rapamycin inhibition of cell motility is a consequence of inhibition of mTOR kinase activity, and results from inhibition of signaling to S6K1 and/or 4E-BP1 established pathways downstream of mTOR, or through a novel pathway signaling through protein phosphatase 2A (PP2A) or other S/T phosphatases (PP4, PP5 and PP6); (2) how inhibition of mTOR by rapamycin prevents IGF-I- stimulated phosphorylation of focal adhesion proteins, including focal adhesion kinase (FAK), p130Cas and paxillin. Data generated from this work will not only provide invaluable insights into the mTOR-mediated signaling pathways, but also make significant contributions to the molecular understanding of tumor cell motility, which is crucial for development of metastasis. The findings may lead to design of novel drugs for the treatment and prevention of metastases.

描述（由申请人提供）：雷帕霉素（MTOR）的哺乳动物靶标控制细胞增殖，生长，分化，运动和生存。与正常细胞相比，患有失调的MTOR信号传导的转化或肿瘤细胞对MTOR抑制剂的敏感性更高，这表明MTOR抑制剂是潜在的肿瘤选择性治疗剂。临床试验表明，雷帕霉素及其衍生物CCI-779，RAD001和AP23573（指定的雷帕霉素）是有前途的抗癌药物。它们特异性地阻止了MTOR的功能，抑制了仅在患者中具有轻微副作用的实体瘤类型的生长。但是，雷帕霉素的抗癌机制仍然晦涩难懂。尽管强烈的研究集中在MTOR在控制细胞增殖和生长中的作用，但对MTOR如何调节细胞运动的作用知之甚少。初步研究表明，雷帕霉素抑制胰岛素样生长因子-L（IGF-I）或10％胎牛血清刺激的肿瘤细胞系在培养中的运动性，这表明MTOR不仅在细胞增殖中，而且在细胞运动中也具有关键作用。申请人的长期目标是了解肿瘤发生和转移中IGF-L-MTOR信号传导的分子机制，从而为肿瘤选择治疗的发展提供了数据。由于IGF-L-MTOR信号通路的失调经常发生在人类肿瘤中，因此拟议的研究将集中于阐明MTOR如何调节IGF-L诱导的细胞运动。结合生化，分子，细胞和遗传方法的结合，该提案的具体目的是确定：（1）雷帕霉素抑制细胞运动的抑制是抑制mTOR激酶活性的结果，以及通过抑制S6K1和/或4E-BP1的信号途径的抑制MTOR激酶的抑制作用，或者是由S6K1和/OR/OR/OR/OR 4E BP1抑制的途径，或者导致的。 2A（PP2A）或其他S/T磷酸酶（PP4，PP5和PP6）； （2）雷帕霉素对MTOR的抑制是如何阻止IGF-I刺激的局灶性粘附蛋白的磷酸化，包括局灶性粘附激酶（FAK），P130CAS和PAXILLIN。这项工作产生的数据不仅将为MTOR介导的信号通路提供宝贵的见解，而且还为对肿瘤细胞运动性的分子理解做出了重要贡献，这对于转移的发展至关重要。这些发现可能导致设计新药物以治疗和预防转移。