title: Down-Regulation of SOX2 Underlies the Inhibitory Effects of the Triphenylmethane Gentian Violet on Melanoma Cell Self-Renewal and Survival.
abstract: Human melanomas contain a population of tumor-initiating cells that are able to maintain the growth of the tumor. We previously showed that the embryonic transcription factor SOX2 is essential for self-renewal and tumorigenicity of human melanoma-initiating cells. However, targeting a transcription factor is still challenging. Gentian violet (GV) is a cationic triphenylmethane dye with potent antifungal and antibacterial activity. Recently, a combination therapy of imiquimod and GV has shown an inhibitory effect against melanoma metastases. Whether and how GV affects melanoma cells remains unknown. Here we show that GV represses melanoma stem cell self-renewal through inhibition of SOX2. Mechanistically, GV hinders EGFR activation and inhibits the signal transducer and activator of transcription-3 [(STAT3)/SOX2] axis. Importantly, we show that GV treatment decreases STAT3 phosphorylation at residue tyrosine 705, thus preventing the translocation of STAT3 into the nucleus and its binding to SOX2 promoter. In addition, GV affects melanoma cell growth by promoting mitochondrial apoptosis and G2 cell cycle arrest. This study shows that in melanoma, GV affects both the stem cell and the tumor bulk compartments, suggesting the potential use of GV in treating human melanoma alone or in combination with targeted therapy and/or immunotherapy.
authors.affiliation: Core Research Laboratory-Istituto Toscano Tumori, Viale Pieraccini 6, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pietrobono
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morandi
authors.affiliation: Core Research Laboratory-Istituto Toscano Tumori, Viale Pieraccini 6, Florence, Italy.
authors.forename: Sinforosa
authors.initials: S
authors.lastname: Gagliardi
authors.affiliation: Plastic Surgery Unit, S.M. Annunziata Hospital-Regional Melanoma Referral Center, Istituto Toscano Tumori, Florence, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Gerlini
authors.affiliation: Plastic Surgery Unit, S.M. Annunziata Hospital-Regional Melanoma Referral Center, Istituto Toscano Tumori, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Borgognoni
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.affiliation: Department of Dermatology, Atlanta Veterans Administration Medical Center, Atlanta, Georgia, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.affiliation: Core Research Laboratory-Istituto Toscano Tumori, Viale Pieraccini 6, Florence, Italy; Department of Oncology, Careggi University Hospital, Florence, Italy. Electronic address: barbara.stecca@ittumori.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Stecca
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005840:Gentian Violet / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D055748:SOXB1 Transcription Factors; D050796:STAT3 Transcription Factor; D005840:Gentian Violet