Rapamycin Potentiates TGFb Tumor Suppressor Function

雷帕霉素增强 TGFb 肿瘤抑制功能

• 批准号: 7225278
• 负责人: Brian K. Law
• 金额: $ 24.56万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225278
• 关键词: Antineoplastic Agents; Binding; Biological Models; Cell Cycle Arrest; Cell Cycle Regulation; Cell Line; Cell Proliferation; Clinical Trials; Cyclin-Dependent Kinases; Dissociation; E2F transcription factors; E2F1 gene; Epithelial Cells; Growth; Human; Human Mammary Carcinoma; Malignant Epithelial Cell; Malignant Neoplasms; Mammary gland; Mediating; Pharmaceutical Preparations; Signal Transduction; Sirolimus; Smad Proteins; Smad protein; Testing; Thinking; Transforming Growth Factor beta; Tumor Suppressor Proteins; cyclin-dependent kinase inhibitor 1B; in vivo; insight; malignant breast neoplasm; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; tumor; tumor growth

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（由申请人提供）：TGFBETA是一种有效的内源性肿瘤抑制剂，几乎所有人类癌症都废除了TGFBETA诱导的生长停滞。令人惊讶的是，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起作用。这些观察结果表明，在人类乳腺癌中，TGFA信号本身并未灭活，而是TGFBETA信号传导与细胞周期调节脱离。我们已经发现，雷帕霉素是一种目前正在临床试验中的抗癌药物，与TGFA合作，诱导正常乳腺上皮细胞的生长停滞，并恢复TGFBETA诱导的MYC，RAS和E2F1中E2F1的细胞周期停滞。雷帕霉素还恢复了几种人类癌细胞系中TGFBETA诱导的生长停滞。雷帕霉素与TGFBETAA合作以抑制细胞增殖，这是由于细胞周期蛋白依赖性激酶CDK2的失活而导致的。 CDK2的抑制与与细胞周期蛋白依赖性激酶抑制剂P27的结合增加有关。我们假设雷帕霉素与TGFBETA发挥作用，可通过增加与p27的关联以及通过E2F转录因子与CDK2的分离来抑制人类乳腺癌细胞的增殖。我们进一步假设，雷帕霉素与TGFBETA合作，存在于体内以抑制肿瘤的生长。这些假设将在以下特定目的中进行测试：1）确定TGFBETA +雷帕霉素治疗的机制，诱导无转化的乳腺上皮细胞和人类乳腺癌细胞的生长停滞，2）确定TGFBETA和RAPAMYCIN调节P27的机制，并检查P27的相互作用，以及3）相互作用。体内的抗肿瘤活动。拟议的研究将利用乳腺癌作为模型系统，但对多种肿瘤类型具有重要意义。这些研究的结果将产生对TGFBETA和雷帕霉素的协同生长抑制机制的重要见解，TGFBETA和雷帕霉素是一种有效的内源性肿瘤抑制剂，以及目前正在针对乳腺癌的临床试验中的药物。

项目成果

Transforming growth factor-beta induces Cdk2 relocalization to the cytoplasm coincident with dephosphorylation of retinoblastoma tumor suppressor protein.

• DOI: 10.1186/bcr762
• 发表时间: 2004
• 期刊: Breast cancer research : BCR
• 作者: Brown KA;Roberts RL;Arteaga CL;Law BK
• 通讯作者: Law BK

Rapamycin disrupts cyclin/cyclin-dependent kinase/p21/proliferating cell nuclear antigen complexes and cyclin D1 reverses rapamycin action by stabilizing these complexes.

• DOI: 10.1158/0008-5472.can-05-1672
• 发表时间: 2006-01-15
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Law, M;Forrester, E;Law, B
• 通讯作者: Law, B

An in vivo model of epithelial to mesenchymal transition reveals a mitogenic switch.

• DOI: 10.1016/j.canlet.2012.08.013
• 发表时间: 2012-12-30
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Jahn, Stephan C.;Law, Mary E.;Corsino, Patrick E.;Parker, Nicole N.;Pham, Kien;Davis, Bradley J.;Lu, Jianrong;Law, Brian K.
• 通讯作者: Law, Brian K.