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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

2013; Wiley; Volume: 280; Issue: 19 Linguagem: Inglês

10.1111/febs.12444

1742-4658

Ana Carolina Ramos Moreno, Renan Orsati Clara, Janine Baptista Coimbra, Ariane Rivellis Julio, Renata Chaves Albuquerque, Edson Mendes de Oliveira, Silvya Stuchi Maria‐Engler, Ana Čampa,

Dermatology and Skin Diseases

Indoleamine 2,3‐dioxygenase 1 ( IDO 1), 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, IDO 1 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 IDO 1, 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 m RNA in fibroblasts and melanocytes. We observed a great variability in the levels of IDO 1 m RNA expression and kynurenine release between skin cells and melanoma cell lines in response to interferon‐γ, a classical IDO 1 inducer. In this setting, melatonin was shown to downregulate kynurenine production. Furthermore, in a condition of low basal activity of IDO 1, 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 IDO 1) 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 .