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

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2011 Feb 25

PMID 21346776

Citations 71

Authors

Deeba N Syed

Farrukh Afaq

Nityanand Maddodi

Jeremy J Johnson

Sami Sarfaraz

Adeel Ahmad

Vijayasaradhi Setaluri

Hasan Mukhtar

Affiliations

Soon will be listed here.

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.

Citing Articles

Fisetin as a chemoprotective and chemotherapeutic agent: mechanistic insights and future directions in cancer therapy.

Fatima R, Soni P, Sharma M, Prasher P, Kaverikana R, Mangalpady S Med Oncol. 2025; 42(4):104.

PMID: 40074915 DOI: 10.1007/s12032-025-02664-x.

Incredible use of plant-derived bioactives as anticancer agents.

Kangra K, Kakkar S, Mittal V, Kumar V, Aggarwal N, Chopra H RSC Adv. 2025; 15(3):1721-1746.

PMID: 39835210 PMC: 11744461. DOI: 10.1039/d4ra05089d.

Therapeutic Potential of Natural Compounds to Modulate WNT/β-Catenin Signaling in Cancer: Current State of Art and Challenges.

Gajos-Michniewicz A, Czyz M Int J Mol Sci. 2024; 25(23).

PMID: 39684513 PMC: 11641450. DOI: 10.3390/ijms252312804.

Aspirin-Fisetin Combinatorial Treatment Exerts Cytotoxic and Anti-Migratory Activities in A375 Malignant Melanoma Cells.

Iftode C, Minda D, Draghici G, Geamantan A, Ursoniu S, Enatescu I Medicina (Kaunas). 2024; 60(7).

PMID: 39064554 PMC: 11278606. DOI: 10.3390/medicina60071125.

Nutritional Strategy for Cancer-From Prevention to Aftercare.

Klekowski J, Chabowski M Nutrients. 2024; 16(10).

PMID: 38794675 PMC: 11123879. DOI: 10.3390/nu16101437.

References

Lu X, Jung J, Cho H, Lim D, Lee H, Chun H . Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J Nutr. 2005; 135(12):2884-90. DOI: 10.1093/jn/135.12.2884. View

Widlund H, Horstmann M, Price E, Cui J, Lessnick S, Wu M . Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor. J Cell Biol. 2002; 158(6):1079-87. PMC: 2173224. DOI: 10.1083/jcb.200202049. View

Spiegelman V, Tang W, Katoh M, Slaga T, Fuchs S . Inhibition of HOS expression and activities by Wnt pathway. Oncogene. 2002; 21(5):856-60. DOI: 10.1038/sj.onc.1205132. View

Khan N, Afaq F, Mukhtar H . Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal. 2007; 10(3):475-510. DOI: 10.1089/ars.2007.1740. View

Larue L, Delmas V . The WNT/Beta-catenin pathway in melanoma. Front Biosci. 2005; 11:733-42. DOI: 10.2741/1831. View

Schepsky A, Bruser K, Gunnarsson G, Goodall J, Hallsson J, Goding C . The microphthalmia-associated transcription factor Mitf interacts with beta-catenin to determine target gene expression. Mol Cell Biol. 2006; 26(23):8914-27. PMC: 1636837. DOI: 10.1128/MCB.02299-05. View

Maddodi N, Huang W, Havighurst T, Kim K, Longley B, Setaluri V . Induction of autophagy and inhibition of melanoma growth in vitro and in vivo by hyperactivation of oncogenic BRAF. J Invest Dermatol. 2010; 130(6):1657-67. PMC: 2869390. DOI: 10.1038/jid.2010.26. View

Johnson J, Syed D, Heren C, Suh Y, Adhami V, Mukhtar H . Carnosol, a dietary diterpene, displays growth inhibitory effects in human prostate cancer PC3 cells leading to G2-phase cell cycle arrest and targets the 5'-AMP-activated protein kinase (AMPK) pathway. Pharm Res. 2008; 25(9):2125-34. PMC: 2994272. DOI: 10.1007/s11095-008-9552-0. View

Govindarajan B, Sligh J, Vincent B, Li M, Canter J, Nickoloff B . Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J Clin Invest. 2007; 117(3):719-29. PMC: 1797605. DOI: 10.1172/JCI30102. View

10.

Perez-Moreno M, Fuchs E . Catenins: keeping cells from getting their signals crossed. Dev Cell. 2006; 11(5):601-12. PMC: 2405914. DOI: 10.1016/j.devcel.2006.10.010. View

11.

Garraway L, Widlund H, Rubin M, Getz G, Berger A, Ramaswamy S . Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005; 436(7047):117-22. DOI: 10.1038/nature03664. View

12.

Syed D, Afaq F, Kweon M, Hadi N, Bhatia N, Spiegelman V . Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. Oncogene. 2006; 26(5):673-82. DOI: 10.1038/sj.onc.1209829. View

13.

Tarapore R, Siddiqui I, Saleem M, Adhami V, Spiegelman V, Mukhtar H . Specific targeting of Wnt/β-catenin signaling in human melanoma cells by a dietary triterpene lupeol. Carcinogenesis. 2010; 31(10):1844-53. PMC: 2950938. DOI: 10.1093/carcin/bgq169. View

14.

Fang D, Hawke D, Zheng Y, Xia Y, Meisenhelder J, Nika H . Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J Biol Chem. 2007; 282(15):11221-9. PMC: 1850976. DOI: 10.1074/jbc.M611871200. View

15.

Maher P, Salgado K, Zivin J, Lapchak P . A novel approach to screening for new neuroprotective compounds for the treatment of stroke. Brain Res. 2007; 1173:117-25. PMC: 2111291. DOI: 10.1016/j.brainres.2007.07.061. View

16.

Takahashi-Yanaga F, Sasaguri T . The Wnt/beta-catenin signaling pathway as a target in drug discovery. J Pharmacol Sci. 2007; 104(4):293-302. DOI: 10.1254/jphs.cr0070024. View

17.

Syed D, Suh Y, Afaq F, Mukhtar H . Dietary agents for chemoprevention of prostate cancer. Cancer Lett. 2008; 265(2):167-76. PMC: 3220618. DOI: 10.1016/j.canlet.2008.02.050. View

18.

Bowerman B . Cell signaling. Wnt moves beyond the canon. Science. 2008; 320(5874):327-8. PMC: 4631219. DOI: 10.1126/science.1157590. View

19.

Kundu J, Surh Y . Breaking the relay in deregulated cellular signal transduction as a rationale for chemoprevention with anti-inflammatory phytochemicals. Mutat Res. 2005; 591(1-2):123-46. DOI: 10.1016/j.mrfmmm.2005.04.019. View

20.

Liu J, Stevens J, Matsunami N, White R . Targeted degradation of beta-catenin by chimeric F-box fusion proteins. Biochem Biophys Res Commun. 2004; 313(4):1023-9. DOI: 10.1016/j.bbrc.2003.12.035. View