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，并且 TGFbeta 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 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发挥作用。这些观察结果表明，在人类乳腺癌中，TGFα信号传导本身并未失活，但TGFβ信号传导变得与细胞周期调节脱钩。我们发现目前处于临床试验阶段的抗癌药物雷帕霉素可以与TGFa协同诱导正常乳腺上皮细胞的生长停滞，并在Myc、Ras和E2F1转化的上皮细胞中恢复TGFbeta诱导的细胞周期停滞。雷帕霉素还能恢复 TGFbeta 诱导的几种人类癌细胞系的生长停滞。雷帕霉素与 TGFbetaa 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 TGFbeta 一起发挥作用，通过增加与 p27 的关联以及通过 E2F 转录因子与 Cdk2 的解离来协同抑制 Cdk2 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 TGFbeta 协同抑制肿瘤生长。这些假设将在以下具体目标中进行测试：1) 确定 TGFbeta + 雷帕霉素治疗诱导未转化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 功能的机制和 3) 检查 TGFbeta 和雷帕霉素体内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，但将对多种肿瘤类型产生重要影响。这些研究的结果将为 TGFbeta 和雷帕霉素（一种有效的内源性肿瘤抑制剂和目前正在进行乳腺癌临床试验的药物）的协同生长抑制机制提供重要见解。

项目成果

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

上皮细胞向间质细胞转变的体内模型揭示了有丝分裂转换。

• 发表时间: 2012-12-30
• 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

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics.

细胞周期蛋白依赖性激酶抑制剂作为抗癌治疗。

• 发表时间: 2015-11
• 影响因子: 3.6
• 作者: Law, Mary E;Corsino, Patrick E;Narayan, Satya;Law, Brian K
• 通讯作者: Law, Brian K

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

转化生长因子-β 诱导 Cdk2 重新定位到细胞质，同时视网膜母细胞瘤肿瘤抑制蛋白去磷酸化。

• 发表时间: 2004
• 作者: Brown, Kimberly A;Roberts, Richard L;Arteaga, Carlos L;Law, Brian K
• 通讯作者: Law, Brian K

Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression.

由 Cdk2 组成型激活引发的肿瘤表现出转化生长因子 β 抗性，并在进展过程中获得旁分泌有丝分裂刺激。

• 发表时间: 2007-04-01
• 影响因子: 11.2
• 作者: Corsino, Patrick;Davis, Bradley;Law, Mary;Chytil, Anna;Forrester, Elizabeth;Norgaard, Peter;Teoh, Nicole;Law, Brian
• 通讯作者: Law, Brian

Mammary tumors initiated by constitutive Cdk2 activation contain an invasive basal-like component.

由 Cdk2 组成型激活引发的乳腺肿瘤含有侵袭性基底细胞样成分。

• 发表时间: 2008-11
• 作者: Corsino, Patrick E;Davis, Bradley J;Nørgaard, Peter H;Parker, Nicole N Teoh;Law, Mary;Dunn, William;Law, Brian K
• 通讯作者: Law, Brian K