Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappa B activation via the NIK/IKK signalling complex

Colorectal cancer is a major cause of cancer deaths in Western countries, b ut epidemiological data suggest that dietary modification might reduce thes e by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of pros taglandin H synthase, which mediates prostaglandin synthesis during inflamm ation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully und erstood. We found that in human colon epithelial cells, curcumin inhibits C OX2 induction by the colon tumour promoters, tumour necrosis factor a or fe capentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induc ed oxidative stress can be mediated by nuclear factor kappa B (NF-kappa B). Since curcumin inhibits NF-kappa B activation, we examined whether its che mopreventive activity is related to modulation of the signalling pathway wh ich regulates the stability of the NF-kappa B-sequestering protein, I kappa B, Recently components of this pathway, NF-kappa B-inducing kinase and I k appa B kinases, IKK alpha and beta, which phosphorylate I kappa B to releas e NF-kappa B, have been characterised, Curcumin prevents phosphorylation of I kappa B by inhibiting the activity of the IKKs, This property, together with a long history of consumption without adverse health effects, makes cu rcumin an important candidate for consideration in colon cancer prevention.