The role of Fas as tumor promoter

Fas作为肿瘤促进剂的作用

• 批准号: 8306703
• 负责人: Marcus E. Peter
• 金额: $ 29.41万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-16 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306703
• 关键词: Address; Apoptosis; Autophagocytosis; CD95 Antigens; Cancer Patient; Cell Death; Cell Line; Cell Size; Cell Survival; Cells; Cessation of life; Citric Acid Cycle; Coupled; Data; Dose; Energy Metabolism; Equilibrium; Event; Genetic; Glutamine; Glycolysis; Growth; Homeostasis; Human; Immune system; In Vitro; Induction of Apoptosis; Inflammation; Ligands; MAPK8 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of ovary; Mediating; Metabolic; Metabolic Pathway; Metabolic stress; Metformin; Modality; Modeling; Mus; Necrosis; Neurons; Oxidative Phosphorylation; Pathway interactions; Phase II Clinical Trials; Physiological; Pre-Clinical Model; Regulation; Reporting; Resistance; Role; Scheme; Signal Transduction; Stem cells; System; TNFRSF6 gene; Testing; Tissues; Transcription Factor AP-1; Tumor Necrosis Factor Ligand Superfamily Member 6; Tumor Promoters; autocrine; base; cancer cell; cancer therapy; cell growth; clinically relevant; energy balance; inhibitor/antagonist; knock-down; migration; mouse model; mutant; neoplastic cell; novel; novel strategies; pre-clinical; prevent; promoter; receptor; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Fas (also called CD95 and APO-1) is a prototypical death receptor that regulates tissue homeostasis primarily in the immune system through induction of apoptosis. During cancer progression, Fas is frequently downregulated, or cells are rendered apoptosis resistant, raising the possibility that loss of Fas is part of a mechanism for tumor evasion. However, complete loss of Fas is rarely seen in human cancers and many cancer cells may express large quantities of Fas, and are highly sensitive to Fas mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for Fas, FasL. These data raised the intriguing possibility that Fas might actually promote the growth of tumors through its nonapoptotic activities. Our recent data have confirmed that cancer cells in general, regardless of their Fas apoptosis sensitivity, depend on constitutive activity of Fas and expression of FasL for optimal growth and survival. Consistently, loss of Fas in mouse models of ovarian cancer and liver cancer prevents or reduces cancer formation, and elimination of FasL in cancer cells causes them to die. Based on these data we propose to study three specific aims: Specific Aim 1: Determine the role of Fas/FasL for the growth and survival of cancer cells. Hypothesis: Fas is a general tumor promoting receptor through a basal activity which involves JNK1 induced AP-1 driven proliferation, and this activity is essential for cancer cell survival. Specific Aim 2: Explore the connection between Fas and energy metabolism. Hypothesis: Regulation of energy metabolism by Fas and FasL is required for tumor cells to grow. Specific Aim 3: Establish preclinical models for the treatment of cancer by blocking the activity of FasL. Hypothesis: Inhibition of FasL rather than the activation of Fas can be used to treat ovarian and liver cancer. The results of this proposal will help delineate the novel activities of Fas as a tumor promoter and are expected to result in a clinically relevant and novel approach to treating cancer.

描述（由申请人提供）：Fas（也称为 CD95 和 APO-1）是一种原型死亡受体，主要通过诱导细胞凋亡来调节免疫系统中的组织稳态。在癌症进展过程中，Fas 经常被下调，或者细胞呈现抗凋亡能力，这增加了 Fas 缺失是肿瘤逃避机制的一部分的可能性。然而，Fas完全丧失在人类癌症中很少见，许多癌细胞可能表达大量Fas，并且在体外对Fas介导的细胞凋亡高度敏感。此外，癌症患者的Fas生理配体FasL水平经常升高。这些数据提出了一个有趣的可能性：Fas 实际上可能通过其非凋亡活性促进肿瘤的生长。我们最近的数据已经证实，一般来说，癌细胞，无论其 Fas 凋亡敏感性如何，都依赖于 Fas 的组成活性和 FasL 的表达来实现最佳生长和存活。一致地，卵巢癌和肝癌小鼠模型中Fas的缺失可以预防或减少癌症的形成，而癌细胞中FasL的消除会导致它们死亡。基于这些数据，我们建议研究三个具体目标： 具体目标 1：确定 Fas/FasL 对癌细胞生长和存活的作用。假设：Fas 是一种通用的肿瘤促进受体，其基础活性涉及 JNK1 诱导的 AP-1 驱动的增殖，并且该活性对于癌细胞的生存至关重要。具体目标2：探索Fas与能量代谢之间的联系。假设：Fas 和 FasL 调节能量代谢是肿瘤细胞生长所必需的。具体目标3：建立通过阻断FasL活性治疗癌症的临床前模型。假设：抑制 FasL 而不是激活 Fas 可用于治疗卵巢癌和肝癌。该提案的结果将有助于描述 Fas 作为肿瘤促进剂的新活性，并有望产生一种临床相关的新型癌症治疗方法。