The inhibitory mechanism of curcumin and its derivative against beta-catenin/Tcf signaling.
We investigated the inhibitory mechanism of curcumin and its derivative (CHC007) against beta-catenin/T-cell factor (Tcf) signaling in various cancer cell lines. Curcumin is known to inhibit beta-catenin/Tcf transcriptional activity in HCT116 cells but not in SW620 cells. To clarify the inhibitory effect of curcumin against beta-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 beta-catenin/Tcf in HEK293 cells transiently transfected with S33Y mutant beta-catenin gene, whose product is not induced to be degraded by adenomatous polyposis coli-Axin-glycogen synthase kinase 3beta complex, we concluded that the inhibitory mechanism was related to beta-catenin itself or downstream components. Western blot analysis suggested that no change in the amount of cytosolic and membranous beta-catenin in a cell occurred; however, nuclear beta-catenin and Tcf-4 proteins were markedly reduced by inhibitors and this lead to the diminished association of beta-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 beta-catenin/Tcf signaling in all tested cancer cell lines and the reduced beta-catenin/Tcf transcriptional activity is due to the decreased nuclear beta-catenin and Tcf-4.
Park
Chi Hoon
CH
Division of Chemistry and Molecular Engineering, Seoul National University, Korea.
Hahm
Eun Ryeong
ER
Park
Seyeon
S
Kim
Hyun-Kyung
HK
Yang
Chul Hak
CH
D001483:Base Sequence; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D003474:Curcumin