Novel Effectors of TGF-beta Signaling in Prostate Growth Regulation and Tumor Pro

前列腺生长调节和肿瘤 Pro 中 TGF-β 信号传导的新型效应器

• 批准号: 7996777
• 负责人: Natasha Kyprianou
• 金额: $ 36.66万
• 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/7996777
• 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。虽然在正常前列腺中起生长抑制/凋亡作用，但衰老前列腺中TGF-β 1的过度产生有助于良性前列腺增生（BPH）和前列腺癌的发展。我们先前已经证实，TGF-β信号的激活导致细胞凋亡诱导，TGF β RII受体（T2 RII）的缺失有助于前列腺肿瘤的生长。T2 RII在人前列腺癌细胞中的过表达能够在体外和体内响应于TGF-β而抑制增殖介导的生长。使用LNCaP T2 RII前列腺癌细胞（雄激素敏感性和TGF-β反应性）作为模型，显示TGF-β 1诱导凋亡，并且这种作用被雄激素增强。最近基于蛋白质组学的方法鉴定了TGF-β通路的两种新的细胞内效应物，其独立于Smads发挥作用以调节前列腺癌细胞中的凋亡结果。在该提案中，我们假设TGF-β 1信号通过Smad 4非依赖性细胞内效应物的变化和与雄激素受体（AR）的串扰调节前列腺生长，并且该网络的功能失活加速恶性表型的表现和肿瘤进展。以下四个具体目标将检验这一假设：具体目标1将表征Smad非依赖性信号传导效应物、抑制素和cofilin作为前列腺良性和恶性上皮细胞中TGF-β作用的新介质的功能参与。具体目标2将确定雄激素受体（AR）在TGF-β 1和雄激素之间的信号相互作用中对前列腺肿瘤上皮细胞凋亡和上皮向间质转化（EMT）的意义。具体目标3将确立cofilin作为前列腺（基质）成纤维细胞在肿瘤微环境中指导TGF-β信号传导能力的新型调节剂的作用。具体目标4将使用条件性敲除小鼠DNT 2 RII表征功能受损的TGF-β信号传导对前列腺生长、肿瘤起始和进展的体内生理学后果，以在与TRAMP转基因小鼠模型杂交时产生双转基因。这些研究将为TGF信号网络的机制失调提供新的见解，该网络有助于前列腺生长和肿瘤进展。了解细胞如何读取TGF-β将能够描绘介导特定TGF-β效应的转录程序，并提供一个框架来定义正常，良性和恶性前前列腺细胞中TGF-β 1生长抑制/凋亡反应的机制，可能被癌细胞中的侵袭性和转移性反应选择性取代。 公共卫生相关性：该申请的长期目标是表征TGF-1和雄激素信号通路之间的功能相互作用，该信号通路独立于Smad效应器，并且在组织微环境的背景下有助于在肿瘤发生和发展期间解除TGF-1介导的对前列腺生长的影响。该申请还将寻求将TGF-β从正常和良性前列腺生长中的肿瘤抑制因子转化为晚期转移性癌症中的肿瘤促进因子的机制。