The expanding roles of 1‐methyl‐tryptophan (1‐MT): in addition to inhibiting kynurenine production, 1‐MT activates the synthesis of melatonin in skin cells

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1), the rate-limiting enzyme of tryptophan catabolism, has been strongly associated with the progression of malignancy and poor survival in melanoma patients. As a result, IDO1 is a leading target for interventions aimed at restoring melanoma immune surveillance. Here, in a scenario involving the tryptophan catabolism, we report that melatonin biosynthesis is driven by 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO1, in human fibroblasts, melanocytes and melanoma cells. In addition to melatonin biosynthesis, 1-MT induced the expression of tryptophan hydroxylase, arylalkylamine-N-acetyltransferase and hydroxyindole O-methyltransferase mRNA in fibroblasts and melanocytes. We observed a great variability in the levels of IDO1 mRNA expression and kynurenine release between skin cells and melanoma cell lines in response to interferon-c, a classical IDO1 inducer. In this setting, melatonin was shown to downregulate kynurenine production. Furthermore, in a condition of low basal activity of IDO1, it was observed that 1-MT, as well melatonin, inhibited the proliferation of human melanoma cells. Taken together, our results suggest that 1-MT may serve as more than just a tool to disrupt tumor immune escape (via the inhibition of IDO1) because it was shown to act directly on the proliferation of human melanoma cells and induce melatonin biosynthesis in the tumor milieu. Moreover, 1-MT-mediated inhibition of IDO occurs in normal skin and melanoma cells, which addresses the possibility that all cells in the skin microenvironment can be targeted by 1-MT. Our findings provide innovative approaches into understanding tumor therapy related to the control of tryptophan metabolism by 1-MT.

The role of melatonin in the light of current knowledge

“…The synthesis of melatonin can occur by alternative O-methylation of serotonin followed by N-acetylation of 5 methoxytryptamine, or O-methylation and then decarboxylation of tryptophan and N-acetylation [3][4][5].…”

“…The process of creating melatonin in the skin is made possible by a high concentration of L-tryptophan molecules, which are the precursors necessary for melatonin biosynthesis. The cutaneous melatoninergic system includes gene expression, protein synthesis, previously mentioned AANAT activity and also hydroxyindole-O-methyltransferase (HIOMT) and tryptophan hydroxylase (TPH) with its isoforms TPH1 and TPH2 [3][4][5].…”

“…1) in the skin takes place in four stages: 1) L-tryptophan (1) in the presence of TPH undergoes hydroxylation to form 5-hydroxytryptophan (2) [3][4][5]. Tryptophan hydroxylase is located in the epidermis and in hair follicles and eccrine sweat glands.…”

“…Furthermore, the skin has the ability to metabolize this hormone. The resulting metabolites, in particular AFMK (N1-acetyl-N2-formyl-5-methoxykynuramine), are extremely potent free radical scavengers [2][3][4]. Especially noteworthy is the antioxidant role of melatonin in the skin.…”

“…Especially noteworthy is the antioxidant role of melatonin in the skin. Presumably due to UV radiation, the skin has developed a specific antioxidant melatoninergic system (MAS), which has a protective role against UV radiation-induced oxidative stress [2][3][4]. There is a hypothesis on the involvement of melatonin, and more specifically MAS, in the pathogenesis of vitiligo.…”