Melatonin Induces Melanogenesis in Human SK-MEL-1 Melanoma Cells Involving Glycogen Synthase Kinase-3 and Reactive Oxygen Species

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.

Identification of L-Cysteinamide as a Potent Inhibitor of Tyrosinase-Mediated Dopachrome Formation and Eumelanin Synthesis

“…Glutathione tripeptide plays a critical role in antioxidant defense, thiol status maintenance, and xenobiotic detoxification [ 44 ]. Previous studies showed that both N-acetyl L-cysteine and glutathione at 5 mM attenuated melatonin-induced melanogenesis in human SK-MEL-1 melanoma cells [ 45 ]. Glutathione, glutathione monoethyl ester, and glutathione disulfide whitened the skin to varying degrees [ 27 , 46 , 47 ].…”

Phenotypic Switching of B16F10 Melanoma Cells as a Stress Adaptation Response to Fe3O4/Salicylic Acid Nanoparticle Therapy

“…On the other hand, previously reported observations have shown the ability of iron to induce cellular oxidative stress through multiple iron-dependent ROS activation mechanisms: apoptosis and necroptosis [ 69 , 70 ], ferroptosis [ 71 ], or pyroptosis [ 72 ]. The increased ROS levels in melanoma cells stimulate melanogenesis [ 73 , 74 , 75 ], an important process that can protect melanoma cells, especially through the free radical scavenging properties [ 49 , 50 , 51 ] and Fe (II) [ 76 ] or Fe (III) [ 77 ] chelating abilities of melanin. Moreover, the ability of melanin to bind Fe (III) ions could be involved in the similar perimembranous arrangement of the SaIONs and melanin deposits, highlighted by microscopy in the Perl Prussian blue-stained samples from the ITO1w group ( Figure 4 h).…”

Role of Amine Neurotransmitters and Their Receptors in Skin Pigmentation: Therapeutic Implication

“…There are reports that melatonin derived from 5-HT induces or inhibits melanogenesis [ 179 , 180 , 181 , 182 ]. This difference seems to be due to the difference in the concentration of melatonin used and the cell line.…”