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

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. He...

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Published in:	The FEBS journal Vol. 280; no. 19; pp. 4782 - 4792
Main Authors:	Moreno, Ana C. R., Clara, Renan O., Coimbra, Janine B., Júlio, Ariane R., Albuquerque, Renata C., Oliveira, Edson M., Maria‐Engler, Silvya S., Campa, Ana
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-10-2013
Subjects:	1‐methyl‐tryptophan Cell Line Cell Line, Tumor Cells Chemical synthesis Humans Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism indoleamine‐2,3‐dioxygenase Kynurenine - metabolism melanoma melatonin Melatonin - metabolism Real-Time Polymerase Chain Reaction Skin Skin - cytology Skin - metabolism skin cells Tryptophan - analogs & derivatives Tryptophan - pharmacology Tumors skin cells 1-methyl-tryptophan melanoma melatonin indoleamine-2,3-dioxygenase
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Summary:	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. 1‐methyl‐tryptophan (1‐MT) may serve as more than just a tool to disrupt tumor immune escape (via the inhibition of indoleamine 2,3‐dioxygenase) because it was shown to directly act on the proliferation of human melanoma cells and induce melatonin biosynthesis in fibroblasts, melanocytes and melanoma cells. We provide novel insights to understand tumor therapy regarding the control of tryptophan metabolism.
ISSN:	1742-464X 1742-4658
DOI:	10.1111/febs.12444