Kebin Liu, PhD, received a 5-year, NCI/NIH R01, “Role of NF-kB in Fas-mediated apoptosis and tumor suppression
Fas is a member of the death receptor superfamily. The major and best known function of Fas is apoptosis. Stimulation of the Fas receptor also activates “non-apoptotic” signaling, notably NF-kB activation. However, the function of Fas-mediated NF-kB activation remains largely unknown. Our preliminary studies demonstrated that canonical NF-kB is a transcription activator of Fas and a promoter of Fas-mediated apoptosis, whereas the alternate NF-kB 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 canonical NF-kB activation results in significantly increased 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-kB 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. 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.