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[Cancer Research 63, 1371-1376, March 15, 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

Synthetic Triterpenoids Enhance Transforming Growth Factor ß/Smad Signaling1

Nanjoo Suh, Anita B. Roberts, Stephanie Birkey Reffey, Kohei Miyazono, Susumu Itoh, Peter ten Dijke, Elke H. Heiss, Andrew E. Place, Renee Risingsong, Charlotte R. Williams, Tadashi Honda, Gordon W. Gribble and Michael B. Sporn2

Dartmouth Medical School and Dartmouth College, Hanover, New Hampshire 03755 [N. S., E. H. H., A. E. P., R. R., C. R. W., T. H., G. W. G., M. B. S.]; National Cancer Institute, NIH, Bethesda, Maryland 20892 [A. B. R., S. B. R.]; Cancer Institute, Tokyo 170-8455, Japan [K. M.]; and The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands [S. I., P. t. D.]

We have studied the effects of two new synthetic triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivative, 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im), on transforming growth factor (TGF)-ß/Smad signaling. These agents, at nanomolar concentrations, increase the expression of TGF-ß-dependent genes, such as those for plasminogen activator inhibitor 1 and the type II TGF-ß receptor, and they synergize with TGF-ß in this regard. They prolong the activation of Smad2 induced by TGF-ß and markedly enhance the ability of Smad3 to activate a Smad binding element, CAGA-luciferase. In transfection assays, they reverse the inhibitory effects of Smad7. CDDO and CDDO-Im also enhance Smad signaling in the pathways of two other members of the TGF-ß superfamily, namely, activin and bone morphogenetic protein. Finally, these triterpenoids induce expression of the transcriptional coactivator p300-CBP-associated factor and synergize with TGF-ß in this regard. These are the first studies to report enhancement of Smad signaling by synthetic triterpenoids and should further their optimal use for applications in prevention or treatment of diseases in which there is aberrant function of TGF-ß.




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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2003 by the American Association for Cancer Research.