TY - JOUR
T1 - Ricinine
T2 - A pyridone alkaloid from Ricinus communis that activates the Wnt signaling pathway through casein kinase 1α
AU - Ohishi, Kensuke
AU - Toume, Kazufumi
AU - Arai, Midori A.
AU - Sadhu, Samir K.
AU - Ahmed, Firoj
AU - Mizoguchi, Takamasa
AU - Itoh, Motoyuki
AU - Ishibashi, Masami
N1 - Funding Information:
We would like to thank Professor Jeremy Nathans (John Hopkins University School of Medicine) for the STF/293 cells and Professor Ronald T. Moon (University of Washington) for the SuperFOPFlash plasmid. This study was supported by KAKENHI Grant numbers 23102008 from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan, 26305001 and 25870128 from the Japan Society for the Promotion of Science (JSPS), Japan, the Cosmetology Research Foundation , the Hamaguchi Foundation for the Advancement of Biochemistry , and the Uehara Memorial Foundation .
PY - 2014/9/1
Y1 - 2014/9/1
N2 - Wnt signaling plays important roles in proliferation, differentiation, development of cells, and various diseases. Activity-guided fractionation of the MeOH extract of the Ricinus communis stem led to the isolation of four compounds (1-4). The TCF/β-catenin transcription activities of 1 and 3 were 2.2 and 2.5 fold higher at 20 and 30 μM, respectively. Cells treated with ricinine (1) had higher β-catenin and lower of p-β-catenin (ser 33, 37, 45, Thr 41) protein levels, whereas glycogen synthase kinase 3β (GSK3β) and casein kinase 1α (CK1α) protein levels remained unchanged. Cells treated with pyrvinium, an activator of CK1α, had lower β-catenin levels. However, the combined treatment of pyrvinium and 1 led to higher β-catenin levels than those in cells treated with pyrvinium alone, which suggested that 1 inhibited CK1α activity. Furthermore, 1 increased β-catenin protein levels in zebrafish embryos. These results indicated that 1 activated the Wnt signaling pathway by inhibiting CK1α.
AB - Wnt signaling plays important roles in proliferation, differentiation, development of cells, and various diseases. Activity-guided fractionation of the MeOH extract of the Ricinus communis stem led to the isolation of four compounds (1-4). The TCF/β-catenin transcription activities of 1 and 3 were 2.2 and 2.5 fold higher at 20 and 30 μM, respectively. Cells treated with ricinine (1) had higher β-catenin and lower of p-β-catenin (ser 33, 37, 45, Thr 41) protein levels, whereas glycogen synthase kinase 3β (GSK3β) and casein kinase 1α (CK1α) protein levels remained unchanged. Cells treated with pyrvinium, an activator of CK1α, had lower β-catenin levels. However, the combined treatment of pyrvinium and 1 led to higher β-catenin levels than those in cells treated with pyrvinium alone, which suggested that 1 inhibited CK1α activity. Furthermore, 1 increased β-catenin protein levels in zebrafish embryos. These results indicated that 1 activated the Wnt signaling pathway by inhibiting CK1α.
KW - Alkaloid
KW - Euphorbiaceae
KW - Ricinus communis
KW - Wnt signal
KW - Zebrafish
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U2 - 10.1016/j.bmc.2014.07.027
DO - 10.1016/j.bmc.2014.07.027
M3 - Article
C2 - 25124862
AN - SCOPUS:84906938582
SN - 0968-0896
VL - 22
SP - 4597
EP - 4601
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 17
ER -