Abstract 2242: Vitamin E δ-tocotrienol inhibits NF-κB activation by up-regulating A20 in macrophages and suppresses colitis-promoted colon tumorigenesis in mice

Abstract

Abstract 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 /γTE ~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. Citation Format: Chao Yang, Qing Jiang. Vitamin E δ-tocotrienol inhibits NF-κB activation by up-regulating A20 in macrophages and suppresses colitis-promoted colon tumorigenesis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2242. doi:10.1158/1538-7445.AM2017-2242