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

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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.