Triterpenoid CDDO-Me blocks the NF-κB pathway by direct inhibition of IKKβ on Cys-179

Abstract

The novel oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO) and the C-28 methyl ester (CDDO-Me) induce apoptosis of human tumor cells by disruption of redox balance and are currently in clinical trials. The present studies show that CDDO and CDDO-Me block tumor necrosis factor α-induced targeting of NF-κB p65 to the nucleus. CDDO-Me also blocked tumor necrosis factor α-induced phosphorylation of IκBα. In concert with these results, we found that CDDO-Me inhibits IκBα kinase β (IKKβ) activity in cells. In support of a direct mechanism, CDDO-Me inhibited recombinant IKKβ activity in vitro. The results also demonstrate that (i) CDDO and CDDO-Me form adducts with IKKβ, but not IKKβ with mutation of Cys-179 to Ala, and (ii) CDDO-Me inhibits IKKβ by a mechanism dependent on oxidation of Cys-179. These findings indicate that CDDO and CDDO-Me directly block IKKβ activity and thereby the NF-κB pathway by interacting with Cys-179 in the IKKβ activation loop. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.