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 Wnt/β-catenin pathway has become an important prognostic marker of melanoma. Here, we show that treatment of 451Lu melanoma cells with the dietary flavonoid fisetin resulted in decreased cell viability with G1-phase arrest and disruption of Wnt/β-catenin signaling. This was accompanied with a decrease in expression of Wnt protein and its co-receptors and 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 GSK3-β assocaited with decreased β-catenin stabilization. Fisetin-mediated interference with the functional cooperation between β-catenin and LEF/TCF-2 resulted in downregulation of positively regulated TCF targets such as c-myc, Brn-2 and Mitf. Flowcytometric analysis of Mitf overexpressing cells showed that fisetin repressed Mitf-induced cell proliferation. Finally, administration of fisetin to 451Lu xenografted nude mice resulted in inhibition of tumor development and decreased Mitf expression. Our data suggest that fisetin can be developed as an effective agent against melanoma due to its potential inhibitory effect on β-catenin/Mitf signaling.

MicroRNA-29a Inhibits Growth, Migration and Invasion of Melanoma A375 Cells in Vitro by Directly Targeting BMI1

“…In melanoma, Wnt/β-catenin signaling directly regulates the expression of microphthalmia transcription factor (MITF), which is a major determinant of both melanocyte development and melanoma development [40][41][42]. Our data displayed that Wnt/β-catenin pathway was inhibited through miR-29a overexpression, which was consistent with the previous study that inhibition of human melanoma cell growth was through disruption of Wnt/β-catenin signaling [43]. We speculated that up-regulating miR-29a possibly repressed melanoma via indirect regulation of MITF and thereby further study about this should be conducted for penetrating investigating the anti-melanoma mechanism of miR-29a.…”

Quercetin potentiates the effect of γδ T cells via modulating the expressions of Granzyme B, perforin and IFN-γ and also regulates the Wnt/β-catenin signalling pathway in human colon cancer cells

“…Fisetin was reported as an inhibitor of Wnt/ -catenin signalling (Syed et al, 2011). Apigenin (40 μM) reduced the levels of -catenin and Dsh proteins and accelerated the degradation of -catenin in the first two hours of treatment promoting cell cycle arrest in breast cancer cells (Song et al, 2000;Landesman-Bollag et al, 2001).…”

Flavonoids: Potential Wnt/beta-catenin signaling modulators in cancer

“…Recently, Fisetin was pointed as an inhibitor of Wnt/β-catening signaling (Syed et al, 2011). Fisetin-treated melanoma cells resulted in decreased cell viability with G1-phase arrest and disruption of Wnt/β-catenin signaling.…”