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GSK-3β-Targeting Fisetin Promotes Melanogenesis in B16F10 Melanoma Cells and Zebrafish Larvae through β-Catenin Activation.

Abstract：

:Fisetin is found in many fruits and plants such as grapes and onions, and exerts anti-inflammatory, anti-proliferative, and anticancer activity. However, whether fisetin regulates melanogenesis has been rarely studied. Therefore, we evaluated the effects of fisetin on melanogenesis in B16F10 melanoma cell and zebrafish larvae. The current study revealed that fisetin slightly suppressed in vitro mushroom tyrosinase activity; however, molecular docking data showed that fisetin did not directly bind to mushroom tyrosinase. Unexpectedly, fisetin significantly increased intracellular and extracellular melanin production in B16F10 melanoma cells regardless of the presence or absence of α-melanocyte stimulating hormone (α-MSH). We also found that the expression of melanogenesis-related genes such as tyrosinase and microphthalmia-associated transcription factor (MITF), were highly increased 48 h after fisetin treatment. Pigmentation of zebrafish larvae by fisetin treatment also increased at the concentrations up to 200 µM and then slightly decreased at 400 µM, with no alteration in the heart rates. Molecular docking data also revealed that fisetin binds to glycogen synthase kinase-3β (GSK-3β). Therefore, we evaluated whether fisetin negatively regulated GSK-3β, which subsequently activates β-catenin, resulting in melanogenesis. As expected, fisetin increased the expression of β-catenin, which was subsequently translocated into the nucleus. In the functional assay, FH535, a Wnt/β-catenin inhibitor, significantly inhibited fisetin-mediated melanogenesis in zebrafish larvae. Our data suggested that fisetin inhibits GSK-3β, which activates β-catenin, resulting in melanogenesis through the revitalization of MITF and tyrosinase.

journal_name

Int J Mol Sci

journal_title

International journal of molecular sciences

authors

Molagoda IMN,Karunarathne WAHM,Park SR,Choi YH,Park EK,Jin CY,Yu H,Jo WS,Lee KT,Kim GY

doi

10.3390/ijms21010312

subject

Has Abstract

pub_date

2020-01-02 00:00:00

issue

issn

1422-0067

pii

ijms21010312

journal_volume

pub_type

杂志文章

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GSK-3β-Targeting Fisetin Promotes Melanogenesis in B16F10 Melanoma Cells and Zebrafish Larvae through β-Catenin Activation.