The Role of Endogenous and Exogenous Melatonin in Cells Derived from Urothelial Tumors. Relevance of MT1 and MT2 Receptors.

Author(s)

Caroline Luísa Quiles

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB)
• Defense date: 2022-08-15

Examining board members

Regina Pekelmann Markus; Debora Rejane Fior Chadi; Selma Maria Bezerra Jeronimo; João Agostinho Machado Neto

• Advisor: Regina Pekelmann Markus

Abstract

Urothelial carcinoma is among the ten most common malignmalignantasia. In silica studies suggested that melatonin synthesized by bladder tumors may have protective effects; however, clinical trials did not confirm the beneficial effects. In this work, we evaluate the effect of exogenous melatonin and the melatonergic system (enzymes, melatonin production and receptors) in three cell lineages: RT4, 5637 and T24. Melatonin local production was observed on a pM scale in all cell lines, and the differential expression of the enzymes involved in its synthesis and metabolism was insufficient to explain the cell lines profile response. Exogenous melatonin at the (mM) decreased viability of all study cell lines. At the same time, the pM-nM range did not modify the proliferative pattern of cell lines, but presented a cell line-specific response in viability: RT4 did not respond to melatonin treatment, increased 5637, and had a dosedependent dual effect of T24 viability. Otherwise, the expression of G-protein coupled melatonin receptors, MT1 and MT2, and the orphan receptor GPR50, which dimerizes with MT1 reducing its affinity to melatonin, opens a new investigative approach. The lower expression of melatonin receptors in RT4 justified the lack of sensitivity to pMnM exogenous melatonin. The differences between 5637 and T24 could also rely on specific receptor expression and localization. The data suggest that in 5637 and T24, MT1 induces an increase in cell viability, while in T24 MT2 membrane receptors decrease cell viability. In summary, here we show for the first time the relevance of melatonin receptor subtypes in promoting fine-tuning of cell viability in bladder cancer. The present study strongly suggests that the therapeutic use of melatonin or analogs in bladder cancer is still premature, and being necessary to adapt the treatment considering the expression of melatonin receptor subtypes for each patient. (AU)

• FAPESP's process: 17/10291-3 - Validating the Prognostic value INDEX based on two genes related to melatonin synthesis and melatonin metabolization in Colorectal and Bladder Cancer
• Grantee: Caroline Luísa Quiles
• Support Opportunities: Scholarships in Brazil - Doctorate