Rapamycin Potentiates TGFb Tumor Suppressor Function

雷帕霉素增强 TGFb 肿瘤抑制功能

• 批准号: 6947331
• 负责人: Brian K. Law
• 金额: $ 25.9万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-22 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947331
• 关键词: breast neoplasms; cell cycle proteins; cell growth regulation; cell proliferation; cyclin dependent kinase; disease /disorder model; drug interactions; enzyme activity; enzyme inhibitors; gel filtration chromatography; gene targeting; genetically modified animals; immunofluorescence technique; immunoprecipitation; kinase inhibitor; laboratory mouse; mammary epithelium; mass spectrometry; neoplasm /cancer pharmacology; neoplastic growth; protein structure function; proteomics; sirolimus; transcription factor; transforming growth factors; tumor suppressor proteins

DESCRIPTION (provided by applicant): TGFbeta is a potent endogenous tumor suppressor and TGFbeta-induced growth arrest is abrogated in almost all human cancers. Strikingly, the Smad proteins thought to mediate TGFa-induced growth arrest are present and functional in most human mammary carcinomas. These observations suggest that in human breast cancer TGFa signaling is not inactivated per se, but that TGFbeta signaling becomes uncoupled from cell cycle regulation. We have discovered that rapamycin, an anti-cancer drug currently in clinical trials, cooperates with TGFa to induce growth arrest of normal mammary epithelial cells, and restores TGFbeta-induced cell cycle arrest in Myc, Ras, and E2F1 transformed epithelial cells. Rapamycin also restores TGFbeta-induced growth arrest in several human carcinoma cell lines. Rapamycin cooperates with TGFbetaa to inhibit cell proliferation, which results from inactivation of the cyclin-dependent kinase Cdk2. Inhibition of Cdk2 is associated with increased binding to the cyclin dependent kinase inhibitor p27. We hypothesize that rapamycin functions with TGFbeta to inhibit the proliferation of human mammary carcinoma cells by cooperatively inhibiting Cdk2 activity through increased association with p27, and through the dissociation of the E2F transcription factor from Cdk2. We further hypothesize that rapamycin cooperates with TGFbeta present in vivo to inhibit tumor growth. These hypotheses will be tested in the following Specific Aims: 1) Determine the mechanisms by which TGFbeta + rapamycin treatment induces growth arrest of no transformed mammary epithelial cells and human mammary carcinoma cells, 2) Determine the mechanisms by which TGFbeta and rapamycin regulate p27 function, and 3) Examine the interaction between TGFbeta and rapamycin anti-tumor activities in vivo. The proposed studies will employ breast cancer as a model system, but will have important implications for a wide array of tumor types. The results of these studies will yield important insights into the synergistic growth inhibitory mechanisms of TGFbeta and rapamycin, a potent endogenous tumor suppressor, and a drug currently in clinical trials against breast cancer, respectively.

描述(申请人提供)：TGFbeta是一种有效的内源性肿瘤抑制因子，TGFbeta诱导的生长抑制在几乎所有人类癌症中都被废除。值得注意的是，被认为介导TGFa诱导的生长停滞的Smad蛋白在大多数人类乳腺癌中都存在并具有功能。这些观察表明，在人类乳腺癌中，TGFa信号本身并不是失活的，而是TGFbeta信号变得不受细胞周期调控的影响。我们发现，目前正在进行临床试验的抗癌药物雷帕霉素与TGFa协同诱导正常乳腺上皮细胞生长停滞，并在Myc、RAS和E2F1转化的上皮细胞中恢复TGFβ诱导的细胞周期停滞。雷帕霉素还可以恢复转化生长因子β诱导的几种人类癌细胞株的生长停滞。雷帕霉素与转化生长因子βA协同作用抑制细胞增殖，这是由于细胞周期蛋白依赖的激酶CDK2失活所致。CDK2的抑制与与细胞周期蛋白依赖的激酶抑制物p27的结合增加有关。我们推测，雷帕霉素与转化生长因子β通过协同抑制CDK2活性，通过增加与p27的结合，以及通过将E2F转录因子从CDK2中解离来抑制人乳腺癌细胞的增殖。我们进一步假设雷帕霉素与体内存在的转化生长因子β相互作用以抑制肿瘤生长。这些假说将在以下特定目的进行检验：1)确定TGFbeta+雷帕霉素治疗诱导NO转化的乳腺上皮细胞和人乳腺癌细胞生长停滞的机制；2)确定TGFbeta和雷帕霉素调节p27功能的机制；3)研究TGFbeta和雷帕霉素体内抗肿瘤活性的相互作用。拟议的研究将以乳腺癌作为模型系统，但将对广泛的肿瘤类型产生重要影响。这些研究的结果将对转化生长因子β和雷帕霉素的协同生长抑制机制产生重要的见解。雷帕霉素是一种有效的内源性肿瘤抑制因子，目前正在进行乳腺癌的临床试验。