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

描述（由申请人提供）：Fas是死亡受体超家族的一员。Fas的主要功能是细胞凋亡。人类FAS或FASL基因编码序列的种系和体细胞突变或缺失可导致自身免疫性淋巴细胞增生性综合征。自身免疫性淋巴细胞增生性综合征患者出现造血和非造血癌症的风险增加。此外，FAS和FASL基因启动子多态性与FAS表达水平降低和人类造血和非造血癌症发展风险增加有关。Fas受体的刺激也激活了“非凋亡”信号，特别是NF-κB的激活。然而，fas介导的NF-κB活化的功能在很大程度上仍然未知。我们的初步研究表明，在人结肠癌细胞和小鼠胚胎成纤维细胞中，典型NF-κB是Fas的转录激活因子和Fas介导的细胞凋亡的启动子，而备选NF-κB是Fas的转录抑制因子和Fas介导的细胞凋亡的抑制因子。此外，我们的初步研究表明，阻断典型的NF-κB活化可显著增加结肠癌细胞在体内的转移潜力。基于这些观察结果，我们假设亚基组成是控制NF-κB蛋白复合物在Fas介导的细胞凋亡中不同功能的分子开关，Fas耐药的药物干预是提高CTL免疫治疗结肠癌转移疗效的有效途径。我们的长期目标是开发一种基于fas的疗法来抑制人类结直肠癌的转移。本项目拟开展三个具体目的：1)验证NF-κB蛋白复合物亚基组成决定NF-κB在结肠癌细胞凋亡和存活中的功能；2)在体内验证NF-κB调控fas介导的凋亡通路介导结肠癌发生的假说；3)验证细胞凋亡致敏化疗提高免疫治疗结肠癌转移疗效的假说。该研究项目有潜力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自发性结肠癌转移的疗效。

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.