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-κB activation. Convincing experimental data have identified NF-κB as a critical promoter of cancer development, creating a solid rationale for the development of antitumor therapy that suppresses NF-κB activity. On the other hand, compelling data have also shown that NF-κB activity enhances tumor cell sensitivity to apoptosis and senescence. Furthermore, although stimulation of Fas activates NF-κB, the function of NF-κB 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-κB activation. Interestingly, canonical NF-κB was found to directly bind to the FAS promoter. Blocking canonical NF-κB activation diminished Fas expression, whereas blocking alternate NF-κB increased Fas expression in human carcinoma cells. Moreover, although canonical NF-κB protected mouse embryo fibroblast (MEF) cells from TNFα-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-κB is a Fas transcription activator and alternate NF-κB is a Fas transcription repressor, and Fas functions as a suppressor of spontaneous sarcoma and colon carcinoma.
Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
Feiyan
F
Liu
Kankana
K
Bardhan
Dafeng
D
Yang
Muthusamy
M
Thangaraju
Vadivel
V
Ganapathy
Jennifer L
JL
Waller
Georgia B
GB
Liles
Jeffrey R
JR
Lee
Kebin
K
Liu
D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008748:Methylcholanthrene / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012509:Sarcoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
C491901:FAS protein, human; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D052003:NF-kappa B p52 Subunit; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; D008748:Methylcholanthrene; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8