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Melatonin, produced by the pineal gland, brain and peripheral organs, displays a diversity of physiological functions including anti-inflammatory, immunomodulatory, and anti-tumor capacities. Herein, we assessed their regulatory effect on melanogenesis using amelanotic (A375, Sk-Mel-28) and highly pigmented (MNT-1, melanotic) human melanoma cell lines. We discovered that subjected compounds decrease the downstream pathway of melanin synthesis by causing a significant drop of cyclic adenosine monophosphate (cAMP) level, the microphthalmia-associated transcription factor (MITF) and resultant collapse of tyrosinase (TYR) activity, and melanin content comparatively to N-phenylthiourea (PTU, a positive control). We observed a reduction in pigment in melanosomes visualized by the transmission electron microscopy. Finally, we assessed the role of G-protein-coupled seven-transmembrane-domain receptors. Obtained results revealed that nonselective MT1 and MT2 receptor antagonist (luzindole) or selective MT2 receptor antagonist (4-P-PDOT) did not affect dysregulation of the melanin pathway indicating a receptor-independent mechanism. Our findings, together with the current state of the art, provide a convenient experimental model to study the complex relationship between metabolites of melatonin and the control of pigmentation serving as a future and rationale strategy for targeted therapies of melanoma-affected patients.<\/jats:p>","DOI":"10.3390\/ijms241914947","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T07:49:29Z","timestamp":1696578569000},"page":"14947","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Melanogenesis Is Directly Affected by Metabolites of Melatonin in Human Melanoma Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Jack K. S.","family":"M\u00f6ller","sequence":"first","affiliation":[{"name":"Department of Dermatology, University of M\u00fcnster, Von-Esmarch-Str. 58, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7029-2657","authenticated-orcid":false,"given":"Kinga","family":"Linowiecka","sequence":"additional","affiliation":[{"name":"Department of Human Biology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1, 87-100 Toru\u0144, Poland"},{"name":"Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5445-8821","authenticated-orcid":false,"given":"Maciej","family":"Gagat","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, 85-092 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3195-9965","authenticated-orcid":false,"given":"Anna A.","family":"Bro\u017cyna","sequence":"additional","affiliation":[{"name":"Department of Human Biology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1, 87-100 Toru\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1338-8230","authenticated-orcid":false,"given":"Marek","family":"Foksi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toru\u0144, 85-092 Bydgoszcz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3070-6349","authenticated-orcid":false,"given":"Agnieszka","family":"Wolnicka-Glubisz","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cancer Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1503-9533","authenticated-orcid":false,"given":"El\u017cbieta","family":"Pyza","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6763-4225","authenticated-orcid":false,"given":"Russel 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