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Vitamin E δ‐tocotrienol inhibits NF‐κB activation by up‐regulating A20 in macrophages and suppresses colitis‐promoted colon tumorigenesis in mice
Author(s) -
Yang Chao,
Jiang Qing
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.135.2
Subject(s) - azoxymethane , iκb kinase , chemistry , nf κb , carcinogenesis , iκbα , inflammation , cancer research , phosphorylation , tumor necrosis factor alpha , nfkb1 , kinase , signal transduction , endocrinology , transcription factor , medicine , biochemistry , biology , gene
Nuclear factor‐κB (NF‐κB) plays a key role in inflammatory responses and cancer development. Inhibition of NF‐κB has been shown to attenuate inflammation and cancer progression. δ‐Tocotrienol (δTE) is a natural vitamin E form rich in annatto seeds and has been shown to inhibit NF‐κB in pancreatic cells. However, potential effect of δTE on NF‐κB activation in immune cells and the underlying mechanism have not been investigated. In the present study, we found that δTE inhibited TNF‐α induced activation of NF‐κB, as indicated by diminished phosphorylation and degradation of IκBα in the cytosol, and phosphorylation of p65 in the nucleus. Furthermore, δTE potently inhibited TNF‐α‐induced phosphorylation of TAK1, a key upstream kinase that is required for the activation of NF‐κB. Interestingly, δTE significantly increased the expression of A20 and CYLD, both of which are negative regulators of NF‐κB. Knockout of A20 partially diminished δTE's anti‐NF‐κB effect, supporting the notion that induction of A20 plays a key role in δTE's anti‐NF‐κB effect. To translate mechanistic findings to a whole body environment, we further investigated the effectiveness of δTE and its metabolite, δTE‐13′‐COOH, against azoxymethane (AOM) induced and colitis‐promoted colon tumorigenesis in male BALB/c mice. We found that δTE‐rich mixed tocotrienols (δTE/ɣTE ~8/1, at 0.035% diet) inhibited colon tumorigenesis, as indicated by 36% reduction of multiplicity of large adenomatous polyps (>2mm(2), P=0.07) and decreased tumor surface area by 31% (P<0.05). δTE‐13′‐COOH (at 0.04% diet) significantly suppressed multiplicity of total polyps by 25% (P=0.06) and large polyps by 54% (P<0.01). Our study demonstrates that δTE has potent anti‐NF‐κB activity and this vitamin E form and its metabolite suppress colitis‐promoted colon tumorigenesis in mice.