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

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 journal › Article › peer-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 language	American English
Pages (from-to)	1371-1376
Number of pages	6
Journal	Cancer Research
Volume	63
Issue number	6
State	Published - Mar 15 2003
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

Cite this

@article{2359f152f598447eb1979afede53dd86,

title = "Synthetic triterpenoids enhance transforming growth factor β/Smad signaling",

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.",

author = "Nanjoo Suh and Roberts, {Anita B.} and Reffey, {Stephanie Birkey} and Kohei Miyazono and Susumu Itoh and {Ten Dijke}, Peter and Heiss, {Elke H.} and Place, {Andrew E.} and Renee Risingsong and Williams, {Charlotte R.} and Tadashi Honda and Gribble, {Gordon W.} and Sporn, {Michael B.}",

year = "2003",

month = mar,

day = "15",

language = "American English",

volume = "63",

pages = "1371--1376",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

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T1 - Synthetic triterpenoids enhance transforming growth factor β/Smad signaling

AU - Suh, Nanjoo

AU - Roberts, Anita B.

AU - Reffey, Stephanie Birkey

AU - Miyazono, Kohei

AU - Itoh, Susumu

AU - Ten Dijke, Peter

AU - Heiss, Elke H.

AU - Place, Andrew E.

AU - Risingsong, Renee

AU - Williams, Charlotte R.

AU - Honda, Tadashi

AU - Gribble, Gordon W.

AU - Sporn, Michael B.

PY - 2003/3/15

Y1 - 2003/3/15

N2 - 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.

AB - 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.

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M3 - Article

C2 - 12649201

SN - 0008-5472

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JO - Cancer Research

JF - Cancer Research

IS - 6

ER -

Synthetic triterpenoids enhance transforming growth factor β/Smad signaling

Abstract

ASJC Scopus subject areas

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