Melanogenesis Is Directly Affected by Metabolites of Melatonin in Human Melanoma Cells

Jack K.S. Möller, Kinga Linowiecka, Maciej Gagat, Anna A. Brożyna, Marek Foksiński, Agnieszka Wolnicka-Glubisz, Elżbieta Pyza, Russel J. Reiter, Meri K. Tulic, Andrzej T. Slominski, Kerstin Steinbrink, Konrad Kleszczyński

Research output: Contribution to journalArticlepeer-review

Abstract

Melatonin (N-acetyl-5-methoxytryptamine, MEL), its kynurenic (N1-acetyl-N2-formyl-5-methoxykynurenine, AFMK) and indolic derivatives (6-hydroxymelatonin, 6(OH)MEL and 5-methoxytryptamine, 5-MT) are endogenously produced in human epidermis. 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.

Original languageEnglish (US)
Article number14947
JournalInternational journal of molecular sciences
Volume24
Issue number19
DOIs
StatePublished - Oct 2023
Externally publishedYes

Keywords

  • G-protein-coupled membrane receptors
  • human melanoma
  • kynurenic and indolic metabolites
  • luzindole
  • melanogenesis
  • melatonin
  • molecular mechanism
  • tyrosinase

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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