GPER como um novo alvo terapêutico no melanoma

Neste trabalho, é descrita pela primeira a vez a expressão do receptor de estrogénios acoplado à proteína G (GPER) numa linha celular de melanoma e que a activação deste receptor pelo agonista G-1 reduz a proliferação celular, sugerindo que o GPER poderá ser um novo alvo terapêutico nesta doença.

Autores e Afiliações:

Mariana P.C. Ribeiro, Armanda E. Santos and José B.A. Custódio

Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.

Abstract:

The activation of the G protein-coupled estrogen receptor (GPER) by its specific agonist G-1 inhibits prostate cancer and 17β-estradiol-stimulated breast cancer cell proliferation. Tamoxifen (TAM), which also activates the GPER, decreases melanoma cell proliferation, but its action mechanism remains controversial. Here we investigated the expression and the effects of GPER activation by G-1, TAM and its key metabolite endoxifen (EDX) on melanoma cells. Mouse melanoma K1735-M2 cells expressed GPER and G-1 reduced cell biomass, and the number of viable cells, without increasing cell death. Rather, G-1 decreased cell division by blocking cell cycle progression in G2. Likewise, TAM and EDX exhibited an antiproliferative activity in melanoma cells due to decreased cell division. Both G-1 and the antiestrogens showed a trend to decrease the levels of phosphorylated ERK 1/2 after 1 h treatment, although only EDX, the most potent antiproliferative antiestrogen, induced significant effects. Importantly, the targeting of GPER with siRNA abolished the cytostatic activity of both G-1 and antiestrogens, suggesting that the antitumor actions of antiestrogens in melanoma cells involve GPER activation. Our results unveil a new target for melanoma therapy and identify GPER as a key mediator of antiestrogen antiproliferative effects, which may contribute to select the patients that benefit from an antiestrogen-containing regimen.

Revista: Chemico-Biological Interactions

Link: https://www.ncbi.nlm.nih.gov/pubmed/28947257