Evaluation of the therapeutic potential of modulating the of immune-pineal axis in...
| Full text | |
| Author(s): |
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]
Total Authors: 8
|
| Affiliation: | [1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Anal & Toxicol, Sao Paulo - Brazil
Total Affiliations: 1
|
| Document type: | Journal article |
| Source: | FEBS Journal; v. 280, n. 19, p. 4782-4792, OCT 2013. |
| Web of Science Citations: | 9 |
| 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-, 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) | |
| FAPESP's process: | 09/53800-9 - Purchase of equipment to setup a Multi-User Laboratory at the University of São Paulo School of Pharmaceutical Sciences |
| Grantee: | Dulcineia Saes Parra Abdalla |
| Support type: | Multi-user Equipment Program |
| FAPESP's process: | 09/14632-3 - Kynurenine versus serotonergic pathway: role in the cross talking of immune cells and in the immune escape of tumors |
| Grantee: | Ana Campa |
| Support type: | Regular Research Grants |
| FAPESP's process: | 10/15919-1 - Tumoral migration and invasion RECK-mediated: melanoma as a model |
| Grantee: | Silvya Stuchi Maria-Engler |
| Support type: | Regular Research Grants |