Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis.
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.
Sung Hee
SH
Choi
Byung-Gyu
BG
Kim
Janet
J
Robinson
Steve
S
Fink
Min
M
Yan
Michael B
MB
Sporn
Sanford D
SD
Markowitz
John J
JJ
Letterio
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects* / Q000378:metabolism*; D003092:Colitis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000378:metabolism; D051901:Smad4 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D016588:Anticarcinogenic Agents; D050791:STAT Transcription Factors; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2