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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

MT1 and MT2 melatonin receptors play opposite roles in brain cancer progression

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Author(s):
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Kinker, G. S. [1] ; Ostrowski, L. H. [1] ; Ribeiro, P. A. C. [2] ; Chanoch, R. [3] ; Muxel, S. M. [1] ; Tirosh, I. [3] ; Spadoni, G. [4] ; Rivara, S. [5] ; Martins, V. R. [2, 6] ; Santos, T. G. [2, 6] ; Markus, R. P. [1] ; Fernandes, P. A. C. M. [1]
Total Authors: 12
Affiliation:
[1] Univ Sao Paulo, Inst Biosci, Dept Physiol, Sao Paulo - Brazil
[2] AC Camargo Canc Ctr, Int Res Ctr, Sao Paulo - Brazil
[3] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot - Israel
[4] Univ Urbino Carlo Bo, Dept Biomol Sci, Urbino - Italy
[5] Univ Parma, Dept Food & Drug, Parma - Italy
[6] INCITO INOTE, Natl Inst Sci & Technol Oncogen & Therapeut Innov, Sao Paulo - Brazil
Total Affiliations: 6
Document type: Journal article
Source: JOURNAL OF MOLECULAR MEDICINE-JMM; v. 99, n. 2 JAN 2021.
Web of Science Citations: 1
Abstract

Primary brain tumors remain among the deadliest of all cancers. Glioma grade IV (glioblastoma), the most common and malignant type of brain cancer, is associated with a 5-year survival rate of < 5%. Melatonin has been widely reported as an anticancer molecule, and we have recently demonstrated that the ability of gliomas to synthesize and accumulate this indolamine in the surrounding microenvironment negatively correlates with tumor malignancy. However, our understanding of the specific effects mediated through the activation of melatonin membrane receptors remains limited. Thus, here we investigated the specific roles of MT1 and MT2 in gliomas and medulloblastomas. Using the MT2 antagonist DH97, we showed that MT1 activation has a negative impact on the proliferation of human glioma and medulloblastoma cell lines, while MT2 activation has an opposite effect. Accordingly, gliomas have a decreased mRNA expression of MT1 (also known as MTNR1A) and an increased mRNA expression of MT2 (also known as MTNR1B) compared to the normal brain cortex. The MT1/MT2 expression ratio negatively correlates with the expression of cell cycle-related genes and is a positive prognostic factor in gliomas. Notably, we showed that functional selective drugs that simultaneously activate MT1 and inhibit MT2 exert robust anti-tumor effects in vitro and in vivo, downregulating the expression of cell cycle and energy metabolism genes in glioma stem-like cells. Overall, we provided the first evidence regarding the differential roles of MT1 and MT2 in brain tumor progression, highlighting their relevance as druggable targets. Key messages center dot MT1 impairs while MT2 promotes the proliferation of glioma and medulloblastoma cell lines. center dot Gliomas have a decreased expression of MT1 and an increased expression of MT2 compared to normal brain cortex. center dot Tumors with a high MT1/MT2 expression ratio have significantly better survival rates. center dot Functional selective drugs that simultaneously activate MT1 and inhibit MT2 downregulate the expression of cell cycle and energy metabolism genes in glioma stem-like cells and exert robust anti-tumor effects in vivo. (AU)

FAPESP's process: 14/23830-1 - Role of melatonine on proliferation and cellular migration in line of human medulloblastoma
Grantee:Luiza Henriques Ostrowski
Support Opportunities: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 14/27287-0 - Characterization of the melatonergic system of human gliomas and its implication on tumor aggressiveness and invasiveness
Grantee:Gabriela Sarti Kinker
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 13/13691-1 - Immune-pineal axis: time-niology integrated to surveillance and defense
Grantee:Regina Pekelmann Markus
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 17/24287-8 - The role of tumor microenvironment elements in malignant cell plasticity and heterogeneity
Grantee:Gabriela Sarti Kinker
Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
FAPESP's process: 14/50943-1 - INCT 2014: on Oncogenomics and Therapeutic Inovations
Grantee:Dirce Maria Carraro
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 15/23348-8 - Evaluation of the therapeutic potential of modulating the of immune-pineal axis in an animal model of lethal systemic inflammation
Grantee:Pedro Augusto Carlos Magno Fernandes
Support Opportunities: Regular Research Grants