Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells.
Dysregulation of Wnt/beta-catenin pathway plays a central role in early events in colorectal carcinogenesis. We examined the effect of quercetin, a famous anti-tumor agent, against beta-catenin/Tcf signaling in SW480 cells. Quercetin inhibited the transcriptional activity of beta-catenin/Tcf in SW480 and also in HEK293 cells transiently transfected with constitutively active mutant beta-catenin gene, whose product is not induced to be degraded by APC-Axin-GSK3beta complex, so we concluded that its inhibitory mechanism was related to beta-catenin itself or downstream components. To investigate the precise inhibitory mechanism, we performed EMSA showing that binding of the Tcf complexes to its specific DNA-binding sites was strongly suppressed by quercetin. Immunoprecipitation analysis also showed that the binding of beta-catenin to Tcf-4 was also disrupted by quercetin. Western blot analysis proved these decreased bindings resulted from decreased level of beta-catenin and Tcf-4 product in nucleus caused by quercetin. Together, we suggest that quercetin is an excellent inhibitor of beta-catenin/Tcf signaling in SW480 cell lines, and the reduced beta-catenin/Tcf transcriptional activity is due to the decreased nuclear beta-catenin and Tcf-4 proteins.
Park
Chi Hoon
CH
Division of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, Republic of Korea.
Chang
Joon Young
JY
Hahm
Eun Ryeong
ER
Park
Seyeon
S
Kim
Hyun-Kyung
HK
Yang
Chul Hak
CH
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011794:Quercetin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D011794:Quercetin