The synthetic triterpenoid CDDO-imidazolide induces monocytic differentiation by activating the Smad and ERK signaling pathways in HL60 leukemia cells

Yan Ji, Hong Jin Lee, Catherine Goodman, Milan Uskokovic, Karen Liby, Michael Sporn, Nanjoo Suh

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Synthetic triterpenoids, CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) or CDDO-imidazolide [2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid imidazolide (CDDO-lm)], induce cell differentiation in myeloid leukemia cells but their mechanism of action is not known. CDDO-lm induces monocytic differentiation markers, CD14, and nonspecific esterase in HL60 leukemia cells. We show that CDDO-lm activates the extracellular signal - regulated kinase (ERK) signaling pathway and up-regulates CCAAT/ enhancer-binding protein β, a transcription factor critical for monocytic differentiation. The monocytic differentiation induced by CDDO-lm was partially blocked by the mitogen-activated protein kinase/ ERK kinase 1 inhibitor PD98059, suggesting that the mitogen-activated protein kinase-ERK 1/2 pathway plays a role in the differentiation induced by CDDO-lm. Furthermore, CDDO-Im activates the transforming growth factor β (TGF-β)/Smad signaling pathway. CDDO-lm enhanced the phosphorylation of the receptor-regulated Smads, phospho-Smad3, and phospho-Smad1/5, but not phospho-Smad2, and induced the expression of Smad4. Monocytic differentiation induced by CDDO-lm was blocked by both TGF-β antibody and the bone morphogenetic protein (BMP) antagonist Noggin. This indicates that activation of the Smad signaling pathway by triterpenoids is an important mechanism of monocytic differentiation. CDDO-lm induced the synthesis of mRNA for TGF-β2, BMP6, TGF-β type II receptor, and BMP type II receptor. CDDO-Im synergized with members of the TGF-β superfamily or with 1α,25(OH)2vitamin D3 (D3) in monocytic differentiation, and the synergistic effect was particularly striking in combination with D3. The combination of triterpenoids and D3 may have a practical use in differentiation therapy of myeloid leukemia as well as for promoting the formation of bone and cartilage.

Original languageEnglish (US)
Pages (from-to)1452-1458
Number of pages7
JournalMolecular Cancer Therapeutics
Volume5
Issue number6
DOIs
StatePublished - Jun 1 2006

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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