Potential therapeutic implications of IL-6/IL-6R/gp130–targeting agents in breast cancer

A novel synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), previously reported to have potent differentiating, antiproliferative, and antiinflammatory activities, has been identified as a ligand for the peroxisome proliferator-activated receptor γ (PPARγ). CDDO induces adipocytic differentiation in 3T3-L1 cells, although it is not as potent as the full agonist of PPARγ, rosiglitazone. Binding studies of CDDO to PPARγ using a scintillation proximity assay give a Ki between 10−8 to 10−7m. In transactivation assays, CDDO is a partial agonist for PPARγ. The methyl ester of CDDO, CDDO-Me, binds to PPARγ with similar affinity, but is an antagonist. Like other PPARγ ligands, CDDO synergizes with a retinoid X receptor (RXR)-specific ligand to induce 3T3-L1 differentiation, while CDDO-Me is an antagonist in this assay. The partial agonism of CDDO and the antagonism of CDDO-Me reflect the differences in their capacity to recruit or displace cofactors of transcriptional regulation; CDDO and rosiglitazone both release the nuclear receptor corepressor, NCoR, from PPARγ, while CDDO-Me does not. The differences between CDDO and rosiglitazone as either partial or full agonists, respectively, are seen in the weaker ability of CDDO to recruit the coactivator CREB-binding protein, CBP, to PPARγ. Our results establish the triterpenoid CDDO as a member of a new class of PPARγ ligands.