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）：TGF β是一种有效的内源性肿瘤抑制因子，TGF β诱导的生长停滞在几乎所有人类癌症中都被消除。引人注目的是，被认为介导TGF α诱导的生长停滞的Smad蛋白在大多数人乳腺癌中存在并起作用。这些观察结果表明，在人类乳腺癌中，TGF α信号传导本身并不失活，但TGF β信号传导与细胞周期调控脱钩。我们已经发现，雷帕霉素，一种目前在临床试验中的抗癌药物，与TGF α合作诱导正常乳腺上皮细胞的生长停滞，并恢复TGF β诱导的Myc，Ras和E2F1转化上皮细胞的细胞周期停滞。雷帕霉素还恢复了几种人类癌细胞系中TGF β诱导的生长停滞。雷帕霉素与TGF β a协同抑制细胞增殖，这是由于细胞周期蛋白依赖性激酶Cdk2失活所致。Cdk2的抑制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TGF β共同作用，通过增加与p27的结合，以及通过E2F转录因子与Cdk2的解离，协同抑制Cdk2的活性，从而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TGF β合作抑制肿瘤生长。这些假设将在以下特定目的中进行检验：1）确定TGF β +雷帕霉素处理诱导未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TGF β和雷帕霉素调节p27功能的机制，和3）检查体内TGF β和雷帕霉素抗肿瘤活性之间的相互作用。拟议的研究将采用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。这些研究的结果将产生重要的见解TGF β和雷帕霉素，一种有效的内源性肿瘤抑制剂，和目前在临床试验中对乳腺癌，分别协同生长抑制机制。

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.