Abstract
Melatonin is present in all living organisms where it displays a diversity of physiological functions. Attenuation of melanogenesis by melatonin has been reported in some mammals and also in rodent melanoma cells. However, melatonin may also stimulate melanogenesis in human melanoma cells through mechanisms that have not yet been revealed. Using the human melanoma cells SK-MEL-1 as a model, an increase in both tyrosinase activity and melanin was already observed at 24 h after melatonin treatment with maximal levels of both being detected at 72 h. This effect was associated with the induction in the expression of the enzymes involved in the synthesis of melanin. In this scenario, glycogen synthase kinase-3β seems to play a significant function since melatonin decreased its phosphorylation and preincubation with specific inhibitors of this protein kinase (lithium or BIO) reduced the expression and activity of tyrosinase. Blocking of PI3K/AKT pathway stimulated melanogenesis and the effect was suppressed by the inhibitors of glycogen synthase kinase-3β. Although melatonin is a recognized antioxidant, we found that it stimulates reactive oxygen species generation in SK-MEL-1 cells. These chemical species seem to be an important signal in activating the melanogenic process since the antioxidants N-acetyl-l-cysteine and glutathione decreased both the level and activity of tyrosinase stimulated by melatonin. Our results support the view that regulation of melanogenesis involves a cross-talk between several signaling pathways.
Highlights
Melatonin is a physiological mediator in animals, bacteria, fungi, and plants [1]
In a previous report we showed that melatonin, used at a high concentration compared to the levels in blood [19], induces melanogenesis through a non-receptor mediated mechanism in SK-MEL-1 cells, a human melanoma cell line with capacity to produce melanin [6]
The results suggest that melatonin modulates the Phosphatidylinositol 3-kinase (PI3K)/AKT pathway and activates GSK-3β in both SK-MEL-1 and MEL-HO melanoma cells
Summary
The pineal gland secretes melatonin into the blood and cerebrospinal fluid to exert a variety of well-documented physiological functions [2]. Among the vast array of biological functions exhibited by melatonin, its antineoplastic properties have attracted significant attention involving cell death, oncostatic properties, and differentiation [3,4,5]. In a previous report on human melanoma cells, we observed that melatonin reduces the number of cells and induces melanogenesis, a complex biosynthetic pathway involving enzymatic and non-enzymatic reactions to produce the skin pigment melanin [6]. Melanin biosynthesis is stimulated by α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH) and non-hormonal effectors, including cAMP elevating agents, glycogen synthase kinase-3 (GSK-3) signaling pathway blocker, and by UV light. The balance of a variety of signal transduction pathways regulates melanogenesis [9]
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