Impact of quercetin and EGCG on key elements of the Wnt pathway in human colon carcinoma cells.
The flavonoids quercetin (QUE) and (-)-epigallocatechin-3-gallate (EGCG) are discussed as potential chemopreventive food constituents. Both compounds have been shown to affect a spectrum of different cellular signaling pathways. Glycogen synthase kinase-3beta (GSK3beta) is one of the key elements of the Wnt pathway, governing beta-catenin homeostasis. The inhibition of GSK3 kinase activity might lead to the onset of beta-catenin/TCF/LEF-mediated gene transcription, representing a potentially mitogenic stimulus. The aim of the study was to elucidate whether QUE and EGCG possibly mediate undesired proliferative stimuli in human colon carcinoma cells by interference with the Wnt pathway. In HT29 cells QUE did not inhibit the activity of GSK3alpha and -beta, measured as phosphorylation at Ser21 and Ser9, respectively. In accordance, QUE did not substantially affect beta-catenin homeostasis. In a reporter gene assay QUE was found to act as a weak inductor of T-cell factor/lymphoid enhancer factor (TCF/LEF) mediated luciferase expression, which was, however, not associated with a stimulation of cell growth. Treatment of HT29 cells with EGCG led to a potent inhibition of GSK3alpha and -beta activity. Subsequently, the amount of phosphorylated beta-catenin was diminished in a concentration-dependent manner. Concomitantly, the overall amount of beta-catenin was decreased to a similar extent, which might result from a downregulation of beta-catenin neogenesis, indicated by reduced levels of beta-catenin mRNA. In accordance, no induction of TCF/LEF-mediated luciferase expression was observed. In conclusion, the results allow the assumption that QUE and EGCG do not mediate proliferative stimuli in HT29 cells by interference with key elements of the Wnt pathway.
Pahlke
Gudrun
G
Institute of Applied Biosciences, Section of Food Toxicology, University of Karlsruhe (TH), Fritz-Haber-Weg 2, 76131 Karlsruhe, Germany. pahlke@lmc.uni-karlsruhe.de
Ngiewih
Yufanyi
Y
Kern
Melanie
M
Jakobs
Sandra
S
Marko
Doris
D
Eisenbrand
Gerhard
G
D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D019073:HT29 Cells; D006706:Homeostasis; D006801:Humans; D011794:Quercetin / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D051153:Wnt Proteins; D051176:beta Catenin; D002392:Catechin; D011794:Quercetin; C045651:epigallocatechin gallate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha