NF-κB Directly Regulates Fas Transcription to Modulate Fas-mediated Apoptosis and Tumor Suppression

Fas is a member of the death receptor family. Stimulation of Fas leads to induction of apoptotic signals, such as caspase 8 activation, as well as non-apoptotic cellular responses, notably NF-kappa B activation. Convincing experimental data have identified NF-kappa B as a critical promoter of cancer development, creating a solid rationale for the development of antitumor therapy that suppresses NF-kappa B activity. On the other hand, compelling data have also shown that NF-kappa B activity enhances tumor cell sensitivity to apoptosis and senescence. Furthermore, although stimulation of Fas activates NF-kappa B, the function of NF-kappa B in the Fas-mediated apoptosis pathway remains largely undefined. In this study, we observed that deficiency of either Fas or FasL resulted in significantly increased incidence of 3-methylcholanthrene-induced spontaneous sarcoma development in mice. Furthermore, Fas-deficient mice also exhibited significantly greater incidence of azoxymethane and dextran sodium sulfate-induced colon carcinoma. In addition, human colorectal cancer patients with high Fas protein in their tumor cells had a longer time before recurrence occurred. Engagement of Fas with FasL triggered NF-kappa B activation. Interestingly, canonical NF-kappa B was found to directly bind to the FAS promoter. Blocking canonical NF-kappa B activation diminished Fas expression, whereas blocking alternate NF-kappa B increased Fas expression in human carcinoma cells. Moreover, although canonical NF-kappa B protected mouse embryo fibroblast (MEF) cells from TNF alpha-induced apoptosis, knocking out p65 diminished Fas expression in MEF cells, resulting in inhibition of FasL-induced caspase 8 activation and apoptosis. In contrast, knocking out p52 increased Fas expression in MEF cells. Our observations suggest that canonical NF-kappa B is a Fas transcription activator and alternate NF-kappa B is a Fas transcription repressor, and Fas functions as a suppressor of spontaneous sarcoma and colon carcinoma.