Synthetic triterpenoids enhance transforming growth factor β/Smad signaling

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, Michael B. Sporn

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

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)-β/Smad signaling. These agents, at nanomolar concentrations, increase the expression of TGF-β-dependent genes, such as those for plasminogen activator inhibitor I and the type II TGF-β receptor, and they synergize with TGF-β in this regard. They prolong the activation of Smad2 induced by TGF-β 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-β superfamily, namely, activin and bone morphogenetic protein. Finally, these triterpenoids induce expression of the transcriptional coactivator p300-CBP-associated factor and synergize with TGF-β 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-β.

Original languageEnglish (US)
Pages (from-to)1371-1376
Number of pages6
JournalCancer Research
Volume63
Issue number6
StatePublished - Mar 15 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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