Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis

J Clin Invest. 2014 Jun;124(6):2472-82. doi: 10.1172/JCI69672. Epub 2014 May 16.

Abstract

Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression of prostaglandin metabolism. Agents that both enhance 15-PGDH expression and suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are a class of small molecules that suppress COX-2 as well as inflammatory cytokine signaling. Here, we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester (CDDO-Me) suppresses CAC in mice. In a spontaneous, inflammation-driven intestinal neoplasia model, deletion of Smad4 specifically in T cells led to progressive production of inflammatory cytokines, including TNF-α, IFN-γ, iNOS, IL-6, IL-1β; as well as activation of STAT1 and STAT3; along with suppression of 15-PGDH expression. Oral administration of CDDO-Me to mice with SMAD4-deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of 15-PGDH. Induction of 15-PGDH by CDDO-Me was dose dependent in epithelial cells and was abrogated following treatment with TGF-β signaling inhibitors in vitro. Furthermore, CDDO-Me-dependent 15-PGDH induction was not observed in Smad3-/- mice. Similarly, CDDO-Me suppressed azoxymethane plus dextran sodium sulfate-induced carcinogenesis in wild-type animals, highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology
  • Carcinogenesis / drug effects*
  • Carcinogenesis / metabolism*
  • Colitis / complications
  • Colitis / metabolism
  • Colitis / pathology
  • Colonic Neoplasms / etiology
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / prevention & control*
  • Cyclooxygenase 2 / biosynthesis
  • Enzyme Induction / drug effects
  • Hydroxyprostaglandin Dehydrogenases / biosynthesis*
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase Type II / biosynthesis
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / pharmacology
  • STAT Transcription Factors / metabolism
  • Smad4 Protein / deficiency
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism

Substances

  • Anticarcinogenic Agents
  • STAT Transcription Factors
  • Smad4 Protein
  • Smad4 protein, mouse
  • Oleanolic Acid
  • bardoxolone methyl
  • Hydroxyprostaglandin Dehydrogenases
  • 15-hydroxyprostaglandin dehydrogenase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2