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

Autor(es)

Moreno, Ana C. R. ^[1] ; Clara, Renan O. ^[1] ; Coimbra, Janine B. ^[1] ; Julio, Ariane R. ^[1] ; Albuquerque, Renata C. ^[1] ; Oliveira, Edson M. ^[1] ; Maria-Engler, Silvya S. ^[1] ; Campa, Ana ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Anal & Toxicol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FEBS Journal; v. 280, n. 19, p. 4782-4792, OCT 2013.
• Citações Web of Science: 9

Resumo

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-, 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. (AU)

• Processo FAPESP: 09/14632-3 - Via das quinureninas versus via serotonérgica: participação na comunicação entre células do sistema imune e no imune escape de tumores
• Beneficiário: Ana Campa
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/15919-1 - Migração e invasão tumoral mediadas pelo gene RECK em modelo de melanoma
• Beneficiário: Silvya Stuchi Maria-Engler
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/53800-9 - EMU: aquisição de equipamentos para compor Laboratório Multiusuário da Faculdade de Ciências Farmacêuticas, Universidade de São Paulo
• Beneficiário: Dulcineia Saes Parra Abdalla
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários