NF-?B directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression.

ABSTRACT: 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-?B activation. Convincing experimental data have identified NF-?B as a critical promoter of cancer development, creating a solid rationale for the development of antitumor therapy that suppresses NF-?B activity. On the other hand, compelling data have also shown that NF-?B activity enhances tumor cell sensitivity to apoptosis and senescence. Furthermore, although stimulation of Fas activates NF-?B, the function of NF-?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-?B activation. Interestingly, canonical NF-?B was found to directly bind to the FAS promoter. Blocking canonical NF-?B activation diminished Fas expression, whereas blocking alternate NF-?B increased Fas expression in human carcinoma cells. Moreover, although canonical NF-?B protected mouse embryo fibroblast (MEF) cells from TNF?-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-?B is a Fas transcription activator and alternate NF-?B is a Fas transcription repressor, and Fas functions as a suppressor of spontaneous sarcoma and colon carcinoma.

SUBMITTER: Liu F 

PROVIDER: S-EPMC3408167 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature