NF-κB directly regulates fas transcription to modulate Fas-mediated apoptosis and tumor suppression

Feiyan Liu, Kankana Bardhan, Dafeng Yang, Muthusamy Thangaraju, Vadivel Ganapathy, Jennifer L Waller, Georgia B. Liles, Jeffrey R Lee, Kebin Liu

Research output: Contribution to journalArticle

76 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)25530-25540
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number30
DOIs
StatePublished - Jul 20 2012

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Transcription
Tumors
Chemical activation
Apoptosis
Fibroblasts
Cells
Caspase 8
Neoplasms
Embryonic Structures
Carcinoma
Sarcoma
Azoxymethane
Colon
Death Domain Receptors
Dextran Sulfate
Methylcholanthrene
Incidence
Colorectal Neoplasms
Recurrence
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

NF-κB directly regulates fas transcription to modulate Fas-mediated apoptosis and tumor suppression. / Liu, Feiyan; Bardhan, Kankana; Yang, Dafeng; Thangaraju, Muthusamy; Ganapathy, Vadivel; Waller, Jennifer L; Liles, Georgia B.; Lee, Jeffrey R; Liu, Kebin.

In: Journal of Biological Chemistry, Vol. 287, No. 30, 20.07.2012, p. 25530-25540.

Research output: Contribution to journalArticle

Liu, Feiyan ; Bardhan, Kankana ; Yang, Dafeng ; Thangaraju, Muthusamy ; Ganapathy, Vadivel ; Waller, Jennifer L ; Liles, Georgia B. ; Lee, Jeffrey R ; Liu, Kebin. / NF-κB directly regulates fas transcription to modulate Fas-mediated apoptosis and tumor suppression. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 30. pp. 25530-25540.
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AU - Ganapathy, Vadivel

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