IKK<alpha> and the control of prostate cancer metastasis

IKK<α>与前列腺癌转移的控制

基本信息

批准号：
7769568
负责人：
Michael Karin
金额：
$ 26.42万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-13 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7769568
关键词：
Ablation Adenocarcinoma Affect Alanine Androgens Arts Behavior Binding Sites Biochemical Cancer Etiology Cancer Patient Carcinoma Cell Line Cell Nucleus Cell Proliferation Cell membrane Cells Chimeric Proteins Collagen Cytoplasm DNA Dendritic Cells Development Distant Down-Regulation Elements Epithelial Cells Epithelium Family Foundations Gene Targeting Genetic Genetic Transcription Glutathione S-Transferase Goals Growth Human IKK alpha Immunoprecipitation Infiltration Inflammation Inflammatory Interferons Knock-out Lymphocyte Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Neoplasm to the Bone Methodology Modeling Molecular Mouse Strains Mus Mutate Mutation Neoplasm Metastasis Normal Cell Nuclear Translocation Oncogenes Operative Surgical Procedures Pathway interactions Patients Peptide Hydrolases Phenocopy Phosphorylation Phosphotransferases Premalignant Primary Neoplasm Proliferating Prostate Prostate carcinoma Prostatic Epithelium Prostatic Neoplasms Protease Inhibitor Protein Biosynthesis Protein Kinase Proteins Proteomics Radiation therapy Rattus Repression Research Research Institute Residual state Role SERPINB5 gene SV40 T Antigens Scanning Serine Protease Serine Proteinase Inhibitors Signal Pathway Site Small Interfering RNA Solid Specimen Staging Stromal Cells T-Lymphocyte TRANCE protein Technology Testing Trans-Activators Transact Transfection Tumor Cell Invasion Tumor Necrosis Factor-Beta Tumor Promotion Up-Regulation Update Urokinase Work activating transcription factor autocrine base cancer cell cell type cytokine effective therapy enhanced green fluorescent protein extracellular human HDAC1 protein in vitro Assay killings macrophage malignant breast neoplasm maspin member mouse model mutant novel novel therapeutic intervention paracrine prevent probasin promoter research study response tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Despite impressive advances in understanding cancer etiology and the development of novel therapeutic approaches, the most effective therapies for solid malignancies (carcinomas) remain surgery and radiotherapy. Although effective in removing and destroying primary tumors, most patients undergoing surgery and radiotherapy will eventually succumb to metastases that develop from residual primary cancer cells that migrate and proliferate at secondary sites. In other words, most cancer patients are killed by metastases rather than the primary tumor. Given the magnitude of this problem, research into the mechanisms that control the metastatic spread of tumors is of utmost importance and urgency This proposal is based on our preliminary results that a mutation that prevents activation of the inflammation responsive protein kinase IkappaB kinase alpha (IKKalpha) results in a dramatic decrease in the metastatic spread of prostate cancer in TRAMP mice, which express a SV40 T antigen oncogene in the prostate epithelium. This reduction in metastatic activity is associated with massive upregulation of maspin, a suppressor of metastasis whose expression is almost completely abolished in primary prostate carcinomas that express the wild type form of IKKalpha. Our preliminary results also suggest that IKKalpha activation results in inhibition of maspin expression. Given its known responsiveness to cytokines produced by stromal cells as well as by inflammatory cells, IKKalpha can provide a major conduit through which the tumor microenvironment controls the metastatic potential of prostate carcinoma cells. Our goal is to test this hypothesis and identify the molecular mechanisms through which IKKalpha controls the metastatic spread of prostate cancer and the expression of maspin in TRAMP mice. We will also examine how the tumor microenvironment modulates the activity of the IKKalpha-maspin axis and will determine the mechanisms through which maspin exerts its anti-metastatic activity in this model of prostate cancer. We will examine whether IKKalpha regulates maspin expression in human prostate cancer specimens and cell lines to control their metastatic and invasive activities. In addition to providing new and important information on the control of tumor metastasis, this work can lay the foundation to the development of novel anti-metastatic therapy based on inhibition of IKKalpha that may be applicable not only to prostate cancer but other cancers as well.

描述（由申请人提供）：尽管了解癌症病因学和新型治疗方法的发展令人印象深刻，但最有效的固体恶性肿瘤疗法（癌）仍然是手术和放射疗法。尽管有效去除和破坏原发性肿瘤，但大多数接受手术和放射疗法的患者最终会屈服于从次要部位迁移和增殖的残留原代癌细胞发展的转移。换句话说，大多数癌症患者被转移而不是原发性肿瘤杀死。考虑到这个问题的严重性，对控制肿瘤转移性传播的机制的研究至关重要，并且紧迫性该提议基于我们的初步结果，即阻止激活炎症蛋白激酶激酶Ikappab激酶激酶激酶alpha（Ikkalpha）的突变导致了一位逐渐减少的散布剂量，从而导致了散布的剂量，从而导致了Sprevication contramant cancer。前列腺上皮中的抗原癌基因。转移活性的这种减少与maspin的大规模上调有关，Maspin是一种转移的抑制剂，其表达几乎完全废除了ikkalpha的野生型形式。我们的初步结果还表明，Ikkalpha激活会导致Maspin表达抑制。鉴于其对基质细胞以及炎症细胞产生的细胞因子的已知反应能力，Ikkalpha可以提供主要的管道，肿瘤微环境控制着前列腺癌细胞的转移潜力。我们的目标是检验这一假设，并确定Ikkalpha控制前列腺癌的转移扩散和MASPIN在流浪汉小鼠中的表达的分子机制。我们还将研究肿瘤微环境如何调节Ikkalpha-Maspin轴的活性，并确定Maspin在这种前列腺癌模型中施加其抗转移活性的机制。我们将检查Ikkalpha是否调节人类前列腺癌标本和细胞系中的Maspin表达以控制其转移性和侵入性活性。除了提供有关控制肿瘤转移的新的重要信息外，这项工作还基于基于抑制Ikkalpha的新型抗转移疗法的基础，不仅适用于前列腺癌，还适用于其他癌症。