Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179.
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 factoralpha-induced targeting of NF-kappaB p65 to the nucleus. CDDO-Me also blocked tumor necrosis factor alpha-induced phosphorylation of IkappaBalpha. In concert with these results, we found that CDDO-Me inhibits IkappaBalpha kinasebeta (IKKbeta) activity in cells. In support of a direct mechanism, CDDO-Me inhibited recombinant IKKbeta activity in vitro. The results also demonstrate that (i) CDDO and CDDO-Me form adducts with IKKbeta, but not IKKbeta with mutation of Cys-179 to Ala, and (ii) CDDO-Me inhibits IKKbeta by a mechanism dependent on oxidation of Cys-179. These findings indicate that CDDO and CDDO-Me directly block IKKbeta activity and thereby the NF-kappaB pathway by interacting with Cys-179 in the IKKbeta activation loop.
Ahmad
Rehan
R
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Raina
Deepak
D
Meyer
Colin
C
Kharbanda
Surender
S
Kufe
Donald
D
D002460:Cell Line; D003545:Cysteine / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000737:chemistry; D013347:Subcellular Fractions / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D051550:I-kappa B Kinase; D003545:Cysteine; D010100:Oxygen