Cancer Cell Overexpression of Death Receptor Modulator

癌细胞过度表达死亡受体调节剂

基本信息

批准号：
8388622
负责人：
FELIPE SAMANIEGO
金额：
$ 20.62万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8388622
关键词：
Accounting Activated Lymphocyte Apoptosis Apoptotic B-Cell Lymphomas B-Lymphocytes Binding CD95 Antigens Cell Death Cell membrane Cell physiology Cell surface Cells Cessation of life Chemotherapy-Oncologic Procedure Complex Development Functional disorder Goals Grant Hematologic Neoplasms Histologic Human Immune system Learning Life Lymphoma Malignant Neoplasms Maps Mediating Mus Proteins Receptor Signaling Regulation Reporter Resistance Role Series Signal Pathway Signal Transduction Surface TNFRSF6 gene Testing Tissues Tumor Necrosis Factor Ligand Superfamily Member 6 United States National Institutes of Health autoimmune lymphoproliferative syndrome base cancer cell cancer therapy cancer type chemotherapy design functional restoration inhibitor/antagonist killings knock-down leukemia/lymphoma mutant neoplastic cell nucleolin overexpression receptor receptor function response selective expression

项目摘要

DESCRIPTION (provided by applicant): Proper development of the immune system involves a series of life-and-death decisions that are mediated through well-orchestrated coordination of signaling pathways, including that of the apoptosis-inducing cell death receptor Fas. Apoptotic signaling mediated by Fas eliminates autoreactive and controls the expansion of activated lymphocytes. Not surprisingly, studies have shown that alterations of Fas receptor signaling pathways promote the development of autoimmune lymphoproliferative syndrome and hematopoietic cancers. Hematopoietic cancer cells commonly express adequate levels of wild-type Fas, but this Fas is often activation-resistant for unknown reasons. Such limitations to our understanding of the mechanisms that cause resistance to apoptosis in leukemias and lymphomas stand in the way of advances in the treatment of these cancers. On the basis of our finding of a virally encoded inhibitor of Fas, we anticipated that cancer cells express similar inhibitors of Fas. Indeed, our search has identified nucleolin as a potential binding inhibitor of Fas. We found that overexpressed nucleolin bound to Fas in lymphoma cells and protected against Fas apoptosis in culture and in mice. Nucleolin knockdown sensitizes the cells to Fas apoptosis. We hypothesize that cell-surface nucleolin interacts directly with Fas and inhibits Fas-mediated apoptosis and that nucleolin represents a feasible target for cancer therapy. To test this hypothesis, we will identify a possible mechanism of nucleolin-mediated regulation of Fas apoptosis in cancer by analyzing Fas signaling in the presence and absence of nucleolin. We will define the Fas-interacting domain on nucleolin and produce mutants that lack binding to Fas. We will express these deletion mutants in mice to determine whether Fas nonbinding nucleolin mutants protect against cell death induced by Fas activation. We will characterize molecular interactions of nucleolin with Fas in cells and mice. This analysis will build on the finding the nucleolin offers resistance to Fas apoptosis. The long-term goal of this project is to develop targeted therapies to directly promote cancer cell apoptosis and greatly enhance current cancer therapies. PUBLIC HEALTH RELEVANCE: Activation of death receptors typically kills cells, but this function is lacking in cancer cells, leading to resistance to chemotherapy. We identified an inhibitor of death receptors nucleolin, which is highly expressed in many cancer cells. We seek to understand the mechanism of how nucleolin blocks death receptors and design strategies to restore death receptor function and to kill tumor cells more efficiently.

描述（由申请人提供）：免疫系统的适当发展涉及一系列生死决策，这些决策是通过信号通路的良好策划协调（包括诱导细胞凋亡的细胞死亡受体FA的）介导的。 FAS介导的凋亡信号传导消除了自动反应性并控制活化的淋巴细胞的膨胀。毫不奇怪，研究表明，FAS受体信号通路的改变促进了自身免疫性淋巴增生性综合征和造血癌的发展。造血癌细胞通常表达足够水平的野生型FA，但由于未知原因，该FA通常是抗激活的。我们对我们对白血病和淋巴瘤抗凋亡的抗性机制的理解的局限性阻碍了这些癌症治疗的进步。根据发现病毒编码的FAS抑制剂，我们预计癌细胞表达了类似的FAS抑制剂。实际上，我们的搜索已确定核儿素是Fas的潜在结合抑制剂。我们发现，过表达的核仁蛋白与淋巴瘤细胞中的FAS结合，并在培养和小鼠中受到防御FAS凋亡的保护。核素敲低使细胞对FAS凋亡敏感。我们假设细胞表面核醇蛋白直接与FAS相互作用，并抑制FAS介导的凋亡，并且核仁素代表了癌症治疗的可行靶标。为了检验这一假设，我们将通过在存在和不存在核醇蛋白的情况下分析FAS信号传导来确定核素介导的FAS凋亡调节的可能机制。我们将定义核仁蛋白上的FAS相互作用结构域，并产生与FAS缺乏结合的突变体。我们将在小鼠中表达这些缺失突变体，以确定FAS非结合核醇突变体是否可以防止FAS激活诱导的细胞死亡。我们将表征细胞和小鼠中FAS核苷的分子相互作用。该分析将基于发现核仁素提供对FAS凋亡的抗性。该项目的长期目标是开发有针对性的疗法，以直接促进癌细胞凋亡并大大增强当前的癌症疗法。公共卫生相关性：激活死亡受体通常会杀死细胞，但是这种功能缺乏癌细胞，从而导致对化疗的抗性。我们确定了死亡受体核苷的抑制剂，该抑制剂在许多癌细胞中高度表达。我们试图了解核仁素如何阻断死亡受体和设计策略的机制，以恢复死亡受体功能并更有效地杀死肿瘤细胞。