2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid and Related Compounds Inhibit Growth of Colon Cancer Cells through Peroxisome Proliferator-Activated Receptor γ-Dependent and -Independent Pathways

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Abstract
2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and the corresponding methyl (CDDO-Me) and imidazole (CDDO-Im) esters induce peroxisome proliferator-activated receptor γ (PPARγ)-dependent transactivation in SW-480 colon cancer cells, and these responses were inhibited by small inhibitory RNA for PPARγ. Moreover, in a mammalian two-hybrid assay using the PPARγ2-VP16 fusion plasmid and GAL4-coactivator/corepressor chimeras and a construct (pGAL4) containing five tandem GAL4 response elements, CDDO, CDDO-Me, and CDDO-IM induce transactivation and PPARγ interaction with multiple coactivators. A major difference among the three PPARγ agonists was the higher activity of CDDO-Im to induce PPARγ interactions with the corepressor SMRT. CDDO, CDDO-Me, and CDDO-Im inhibited SW-480, HCT-116, and HT-29 colon cancer cell proliferation at low concentrations and induced cell death at higher concentrations. Growth inhibition at lower concentrations correlated with induction of the tumor suppressor gene caveolin-1 which is known to inhibit colon cancer cell growth. Induction of caveolin-1 by CDDO, CDDO-Me, and CDDO-Im was inhibited by the PPARγ antagonist N-(4′-aminopyridyl-2-chloro-5-nitrobenzamide (T007), whereas higher doses induced apoptosis [poly(ADP-ribose) polymerase cleavage], which was not inhibited by T007. These results illustrate that CDDO-, CDDO-Me, and CDDO-Im induce both PPARγ-dependent and -independent responses in colon cancer cells, and activation of these pathways are separable and concentration-dependent for all three compounds.

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