Role of NF-kB in Fas-mediated Apoptosis and Tumor Suppression

NF-kB 在 Fas 介导的细胞凋亡和肿瘤抑制中的作用

• 批准号: 9114501
• 负责人: KEBIN LIU
• 金额: $ 31.54万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114501
• 关键词: Apoptosis; Apoptosis Promoter; Apoptotic; CD95 Antigens; Cell Survival; Cell surface; Cells; Cessation of life; Code; Colon Carcinoma; Colorectal Cancer; Complex; Data; Data Set; Databases; Development; Embryo; Exhibits; Fibroblasts; Genes; Genetic Polymorphism; Genetic Transcription; Germ-Line Mutation; Goals; Health; Hematologic Neoplasms; Human; Immunotherapy; Intervention; Lead; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Methylation; Molecular; Molecular Analysis; Mus; NF-kappa B; Neoplasm Metastasis; Nuclear; Patients; Physiological; Proteins; Regulation; Research Project Grants; Resistance; Risk; Role; Signal Transduction; Somatic Mutation; Specificity; Syndrome; T-Lymphocyte; TNF gene; TNFRSF6 gene; TNFSF6 gene; Testing; Therapeutic Intervention; Transcription Coactivator; Transcription Repressor/Corepressor; Tumor Suppression; Tumor Suppressor Proteins; autoimmune lymphoproliferative syndrome; base; cancer cell; cancer genomics; chemotherapy; histone methyltransferase; in vivo; member; neoplastic cell; promoter; protein complex; receptor; tumor; verticillin A

DESCRIPTION (provided by applicant): Fas is a member of the death receptor superfamily. The major and best known function of Fas is apoptosis. Germline and somatic mutations or deletions of FAS or FASL gene coding sequences in humans lead to autoimmune lymphoproliferative syndrome. Patients with autoimmune lymphoproliferative syndrome exhibit increased risk of both hematopoietic and non-hematopoietic cancers. Furthermore, FAS and FASL gene promoter polymorphisms are associated with decreased Fas expression level and increased risk of both hematopoietic and non-hematopoietic cancer developments in humans. Stimulation of Fas receptor also activates "non-apoptotic" signaling, notably NF-κB activation. However, the function of Fas-mediated NF-κB activation remains largely unknown. Our preliminary studies demonstrated that canonical NF-κB is a transcription activator of Fas and a promoter of Fas-mediated apoptosis, whereas the alternate NF-κB is a transcription repressor of Fas and suppressor of Fas-mediated apoptosis in both human colon carcinoma cells and in mouse embryonic fibroblasts. Furthermore, our preliminary studies demonstrated that blocking the canonical NF-κB activation results in a significantly increase of colon carcinoma cell metastatic potential in vivo. Based on these observations, we hypothesize that subunit composition is the molecular switch that controls the contrasting functions of the NF-κB protein complexes in Fas-mediated apoptosis and pharmacological intervention of Fas resistance is an effective approach to increase CTL immunotherapy efficacy against colon cancer metastasis. Our long-term goal is to develop a Fas-based therapy to suppress human colorectal cancer metastasis. We propose to carry out three specific aims in this project: 1) test the hypothesis that subunit composition of the NF-κB protein complex determines NF-κB functions in colon carcinoma cell apoptosis and survival; 2) test the hypothesis that NF-κB regulates Fas-mediated apoptosis pathways to mediate colon carcinoma development in vivo; and 3) test the hypothesis that apoptosis sensitization chemotherapy increases the efficacy of immunotherapy against colon carcinoma metastasis. This research project has the potential to develop an adjunct therapy to overcome Fas resistance to increase the efficacy of immunotherapy for effective suppression of spontaneous colon cancer metastasis.

描述（由适用提供）：FAS是死亡受体超家族的成员。 FAS的主要和最著名的功能是凋亡。人类中FAS或FAS基因编码序列的种系和体细胞突变或缺失导致自身免疫性淋巴细胞增生综合征。自身免疫性淋巴细胞增生综合征暴露的患者会增加造血和非造血性癌的风险。此外，FAS和FASL基因启动子多态性与FAS表达水平降低以及人类造血和非造血性癌症发展的风险增加有关。 FAS受体的刺激还激活了“非凋亡”信号传导，尤其是NF-κB激活。然而，FAS介导的NF-κB激活的功能在很大程度上仍然未知。我们的初步研究表明，规范的NF-κB是FAS的转录激活剂，也是Fas介导的凋亡的启动子，而替代NF-κB是FAS的转录反射器，也是Fas介导的两个人类结肠癌细胞和小鼠胚胎纤维纤维纤维纤维纤维细胞中Fas介导的凋亡的抑制剂。此外，我们的初步研究表明，阻断规范的NF-κB激活导致体内结肠癌细胞转移性潜力的显着增加。基于这些观察结果，我们假设亚基组成是控制FAS介导的凋亡中NF-κB蛋白复合物的对比功能的分子开关，而FAS耐药性的药物干预是提高CTL免疫疗法对Colon Cancor Cancer Cancer Cancerasisis的有效方法。我们的长期目标是开发一种基于FAS的疗法来抑制人类有色癌症转移。我们建议在该项目中执行三个具体目标：1）测试NF-κB蛋白复合物的亚基组成的假设决定了结肠癌细胞凋亡和存活中NF-κB的功能； 2）检验了NF-κB调节FAS介导的凋亡途径以介导体内结肠癌发育的假设； 3）检验了凋亡敏感性化学疗法的假设提高了对结肠癌转移的免疫疗法的效率。该研究项目有可能开发一种辅助疗法来克服FAS耐药性，以提高免疫疗法有效抑制赞助商结肠癌转移的有效性。