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

Autor(es):Mostrar menos -

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF MOLECULAR MEDICINE-JMM; v. 99, n. 2 JAN 2021.
• Citações Web of Science: 1

Resumo

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)

• Processo FAPESP: 14/23830-1 - Papel da melatonina sobre a proliferação e migração celular em linhagem de meduloblastoma humano
• Beneficiário: Luiza Henriques Ostrowski
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 14/27287-0 - Caracterização do sistema melatonérgico de gliomas humanos e sua implicação sobre o grau de agressividade e invasibilidade tumoral
• Beneficiário: Gabriela Sarti Kinker
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 13/13691-1 - Eixo imune-pineal: integrando a biologia do tempo em condições fisiológicas, fisiopatológicas e patológicas
• Beneficiário: Regina Pekelmann Markus
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/24287-8 - O papel de elementos do microambiente tumoral na plasticidade e heterogeneidade de células malignas
• Beneficiário: Gabriela Sarti Kinker
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto
• Processo FAPESP: 14/50943-1 - INCT 2014: de Oncogenômica e Inovação Terapêutica
• Beneficiário: Dirce Maria Carraro
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/23348-8 - Avaliação do potencial terapêutico da modulação do eixo imune-pineal em modelo animal de inflamação sistêmica letal
• Beneficiário: Pedro Augusto Carlos Magno Fernandes
• Modalidade de apoio: Auxílio à Pesquisa - Regular