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-γ, 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.