title: Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/β-catenin signaling and decreased Mitf levels.
abstract: The prognosis of advanced melanoma remains poor in spite of treatment advances, emphasizing the importance of additional preventive measures. Flavonoids, natural components of our diet, are being investigated for their chemopreventive/therapeutic properties. Microphthalmia-associated transcription factor (Mitf), downstream of the Wnt/β-catenin pathway, has become an important prognostic marker of melanoma. In this study, we show that treatment of 451Lu melanoma cells with the dietary flavonoid fisetin (3,7,3',4'-tetrahydroxyflavone) resulted in decreased cell viability with G1-phase arrest and disruption of Wnt/β-catenin signaling. This was accompanied by a decrease in the expression of Wnt protein and its co-receptors, as well as by a parallel increase in the expression of endogenous Wnt inhibitors. Fisetin-treated cells showed increased cytosolic levels of Axin and β-TrCP and decreased phosphorylation of glycogen synthase kinase 3β associated with decreased β-catenin stabilization. Fisetin-mediated interference with the functional cooperation between β-catenin and T-cell factor (TCF)-2 resulted in the downregulation of positively regulated TCF targets, such as c-myc, Brn-2, and Mitf. Flow-cytometric analysis of Mitf-overexpressing cells showed that fisetin repressed Mitf-induced cell proliferation. Finally, administration of fisetin to 451Lu-xenografted nude mice resulted in the inhibition of tumor development and decreased Mitf expression. Our data suggest that fisetin can be developed as an effective agent against melanoma because of its potential inhibitory effect on β-catenin/Mitf signaling.
authors.affiliation: Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Deeba N
authors.initials: DN
authors.lastname: Syed
authors.forename: Farrukh
authors.initials: F
authors.lastname: Afaq
authors.forename: Nityanand
authors.initials: N
authors.lastname: Maddodi
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Johnson
authors.forename: Sami
authors.initials: S
authors.lastname: Sarfaraz
authors.forename: Adeel
authors.initials: A
authors.lastname: Ahmad
authors.forename: Vijayasaradhi
authors.initials: V
authors.lastname: Setaluri
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D016193:G1 Phase / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D051539:Hepatocyte Nuclear Factor 1-beta / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000032:analysis / Q000502:physiology*; D044844:beta-Transducin Repeat-Containing Proteins / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D005419:Flavonoids; D044948:Flavonols; C496495:HNF1B protein, human; D051739:Microphthalmia-Associated Transcription Factor; D051153:Wnt Proteins; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C017875:fisetin