Inhibition of Human Melanoma Cell Growth by the Dietary Flavonoid Fisetin Is Associated with Disruption of Wnt/β-Catenin Signaling and Decreased Mitf Levels

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.