The synthetic triterpenoid CDDO-imidazolide induces monocytic differentiation by activating the Smad and ERK signaling pathways in HL60 leukemia cells.
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-Im)], induce cell differentiation in myeloid leukemia cells but their mechanism of action is not known. CDDO-Im induces monocytic differentiation markers, CD14, and nonspecific esterase in HL60 leukemia cells. We show that CDDO-Im activates the extracellular signal-regulated kinase (ERK) signaling pathway and up-regulates CCAAT/enhancer-binding protein beta, a transcription factor critical for monocytic differentiation. The monocytic differentiation induced by CDDO-Im was partially blocked by the mitogen-activated protein kinase/ERK kinase 1 inhibitor PD98059, suggesting that the mitogen-activated protein kinase-ERK1/2 pathway plays a role in the differentiation induced by CDDO-Im. Furthermore, CDDO-Im activates the transforming growth factor beta (TGF-beta)/Smad signaling pathway. CDDO-Im 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-Im was blocked by both TGF-beta 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-Im induced the synthesis of mRNA for TGF-beta2, BMP6, TGF-beta type II receptor, and BMP type II receptor. CDDO-Im synergized with members of the TGF-beta superfamily or with 1alpha,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.
Ji
Yan
Y
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Lee
Hong Jin
HJ
Goodman
Catherine
C
Uskokovic
Milan
M
Liby
Karen
K
Sporn
Michael
M
Suh
Nanjoo
N
D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053781:Transforming Growth Factor beta2; D000099176:Noggin Protein
D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; D002117:Calcitriol; D002352:Carrier Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D007093:Imidazoles; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009828:Oleanolic Acid; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D000099176:Noggin Protein; C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; C525816:BMP6 protein, human; C509041:TGFB2 protein, human