TGF-Beta Signaling Effectors in Prostate Growth Regulation/Tumor Progression

前列腺生长调节/肿瘤进展中的 TGF-β 信号传导效应器

• 批准号: 8129554
• 负责人: Natasha Kyprianou
• 金额: $ 30.1万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129554
• 关键词: Actins; Adhesions; Aging; Androgen Receptor; Androgens; Apoptosis; Apoptosis Promoter; Apoptotic; Benign; Benign Prostatic Hypertrophy; Bypass; Cells; Complex; Cytoskeleton; Defect; Development; Disseminated Malignant Neoplasm; Dominant-Negative Mutation; Embryonic Development; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Event; Extracellular Matrix; Family; Fibroblasts; Genetic Transcription; Goals; Growth; Growth Factor; Human; In Vitro; Induction of Apoptosis; Inhibition of Apoptosis; Knockout Mice; LNCaP; Laboratories; Ligands; Link; MAP Kinase Gene; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Modeling; Molecular; Neoplasm Metastasis; Outcome; Pathway interactions; Phosphotransferases; Physiological; Physiological Processes; Premalignant; Prostate; Prostatic Neoplasms; Proteins; Proteomics; Reading; Receptor Signaling; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Transgenic Organisms; Tumor Promoters; Tumor Suppressor Proteins; Tumorigenicity; Work; Wound Healing; base; cancer cell; cell growth; cell motility; cofilin; epithelial to mesenchymal transition; evidence base; in vivo; insight; malignant phenotype; migration; mouse model; novel; overexpression; programs; prohibitin; promoter; public health relevance; receptor; response; trafficking; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Transforming growth factor-¿ (TGF-¿) is a negative regulator of normal, benign and malignant prostate growth. While serving a growth-inhibitory/apoptotic role in the normal prostate, overproduction of TGF- ¿ 1 in the aging prostate contributes to the development of benign prostate hyperplasia (BPH) and prostate cancer. We previously established that activation of TGF-s ¿ signaling leads to apoptosis induction and loss of TGF ¿ RII receptor (T2RII) contributes to prostate tumorigenic growth. Overexpression of T2RII in human prostate cancer cells enables apoptosis-mediated-growth suppression in response to TGF- ¿ in vitro and in vivo. Using the LNCaP T2RII prostate cancer cells (androgen-sensitive and TGF- ¿ responsive) as a model, it was shown that TGF- ¿1 induces apoptosis and this effect was enhanced by androgens. Recent proteomic-based approaches identified two new intracellular effectors of TGF-¿ pathway that act independent of Smads to regulate apoptotic outcomes in prostate cancer cells. In this proposal we hypothesize that TGF- ¿ 1 signaling via changes in Smad4-independent intracellular effectors and cross-talk with the androgen receptor (AR) regulates prostate growth, and functional inactivation of this network accelerates the manifestation of the malignant phenotype and tumor progression. The following four Specific Aims will test this hypothesis: Specific Aim 1 will characterize the functional involvement of Smad- independent signaling effectors, prohibitin and cofilin, as novel mediators of TGF-¿ action in prostate benign and malignant epithelial cells. Specific Aim 2 will identify the significance of the androgen receptor (AR) in the signaling interaction between TGF-¿1 and androgens towards apoptosis and epithelial to mesenchymal transition (EMT) of prostate tumor epithelial cells. Specific Aim 3 will establish the role of cofilin as a novel regulator of the ability of prostate (stroma) fibroblasts to direct TGF- ¿ signaling, in the context of the tumor microenvironment. Specific Aim 4 will characterize the in vivo physiological consequences of a functionally impaired TGF-¿ signaling on prostate growth, tumor initiation and progression using a conditional knockout mouse DNT2RII, to generate double transgenics upon crossing with the TRAMP transgenic mouse model. These studies will provide new insights into the mechanistic deregulation of TGF¿ signaling network that contributes to prostate growth and tumor progression. Understanding how cells read TGF- ¿ will enable both the delineation of the transcriptional programs that mediate specific TGF- ¿ effects and provide a framework for defining the mechanism via which TGF- ¿ 1 growth inhibitory/apoptotic responses in normal, benign and pre-malignant prostate cells, might be selectively replaced by invasive and metastatic responses in cancer cells. PUBLIC HEALTH RELEVANCE: The long term objective of the application is to characterize the functional interplay between the TGF- ¿ 1 and androgen signaling pathways that independently of Smad effectors and in the context of tissue microenvironment contribute to deregulation of TGF ¿ 1 mediated effects on prostate growth during tumor initiation and progression. The application will also pursue the mechanism converting TGF- ¿ from a tumor suppressor in normal and benign prostate growth, to a tumor promoter in advanced metastatic cancer.

描述（由申请人提供）：转化生长因子-¿ (TGF-¿) 是正常、良性和恶性前列腺生长的负调节因子，同时在正常前列腺中发挥生长抑制/凋亡作用，TGF-¿ 1 老化前列腺中的 TGF-s 的激活会导致良性前列腺增生 (BPH) 和前列腺癌的发生。信号传导导致细胞凋亡诱导和 TGF 丧失 ¿ RII 受体 (T2RII) 有助于人前列腺癌细胞中 T2RII 的过度表达，从而能够响应 TGF-¿使用 LNCaP T2RII 前列腺癌细胞（雄激素敏感且 TGF-¿ 反应性）作为模型，结果表明 TGF- ¿ 1 诱导细胞凋亡，并且雄激素增强了这种作用。最近基于蛋白质组学的方法鉴定了两种新的 TGF-¿独立于 Smad 发挥作用来调节前列腺癌细胞凋亡结果的途径在本提案中，我们采用了 TGF-¿ 1 信号通过不依赖于 Smad4 的细胞内效应器的变化以及与雄激素受体 (AR) 的串扰来调节前列腺生长，并且该网络的功能失活加速了恶性表型的表现和肿瘤进展，以下四个具体目标将对此进行测试。假设：特定目标 1 将表征 Smad 独立信号传导效应器、抑制素和丝切蛋白的功能参与，作为 TGF-¿具体目标 2 将确定雄激素受体 (AR) 在 TGF-¿ 之间信号传导相互作用中的重要性。 1 和雄激素对前列腺肿瘤上皮细胞的凋亡和上皮间质转化 (EMT) 的影响 具体目标 3 将确立肌动蛋白丝切蛋白作为前列腺（间质）成纤维细胞引导 TGF-¿具体目标 4 将描述功能受损的 TGF-¿ 的体内生理后果。使用条件敲除小鼠 DNT2RII 来控制生长、肿瘤发生和进展的信号传导，在与 TRAMP 转基因小鼠模型杂交时产生双转基因。这些研究将为 TGF 的机制失调提供新的见解。有助于前列腺生长和肿瘤进展的信号网络。了解细胞如何读取 TGF- ¿将能够描述介导特定 TGF-¿ 的转录程序效应并提供一个框架来定义 TGF-¿ 1 正常、良性和癌前前列腺细胞中的生长抑制/凋亡反应可能会选择性地被癌细胞中的侵袭性和转移性反应所取代。 公共卫生相关性：该应用程序的长期目标是表征 TGF-¿ 1 和雄激素信号通路独立于 Smad 效应器并且在组织微环境的背景下有助​​于 TGF 的失调 ¿ 1 在肿瘤发生和进展过程中对前列腺生长的介导作用该应用还将探索转化 TGF-¿从正常和良性前列腺生长的肿瘤抑制因子，到晚期转移性癌症的肿瘤促进因子。