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The inhibitory mechanism of curcumin and its derivative against β‐catenin/Tcf signaling
Author(s) -
Park Chi Hoon,
Hahm Eun Ryeong,
Park Seyeon,
Kim Hyun-Kyung,
Yang Chul Hak
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.04.013
Subject(s) - curcumin , catenin , wnt signaling pathway , adenomatous polyposis coli , western blot , transfection , chemistry , microbiology and biotechnology , signal transduction , cell culture , gsk 3 , immunoprecipitation , biology , biochemistry , gene , cancer , genetics , colorectal cancer
We investigated the inhibitory mechanism of curcumin and its derivative (CHC007) against β‐catenin/T‐cell factor (Tcf) signaling in various cancer cell lines. Curcumin is known to inhibit β‐catenin/Tcf transcriptional activity in HCT116 cells but not in SW620 cells. To clarify the inhibitory effect of curcumin against β‐catenin/Tcf signaling, we tested several cancer cell lines. In addition, in order to verify the inhibitory mechanism, we performed reporter gene assay, Western blot, immunoprecipitation, and electrophoretic mobility shift assay. Since inhibitors downregulated the transcriptional activity of β‐catenin/Tcf in HEK293 cells transiently transfected with S33Y mutant β‐catenin gene, whose product is not induced to be degraded by adenomatous polyposis coli–Axin–glycogen synthase kinase 3β complex, we concluded that the inhibitory mechanism was related to β‐catenin itself or downstream components. Western blot analysis suggested that no change in the amount of cytosolic and membranous β‐catenin in a cell occurred; however, nuclear β‐catenin and Tcf‐4 proteins were markedly reduced by inhibitors and this lead to the diminished association of β‐catenin with Tcf‐4 and to the reduced binding to the consensus DNA. In the present study, we demonstrate that curcumin and its derivative are excellent inhibitors of β‐catenin/Tcf signaling in all tested cancer cell lines and the reduced β‐catenin/Tcf transcriptional activity is due to the decreased nuclear β‐catenin and Tcf‐4.