Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5559354 | Chemico-Biological Interactions | 2017 | 9 Pages |
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.
Keywords
ECFSRBCyPDTTTBSERKBCAPAGEPMSFPI3KGPCR3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromidePKCGPERTMBIGF-1RGPR30FBSPVDFDMEMPBSEDX3,3′,5,5′-tetramethylbenzidine5-bromo-2′-deoxyuridineDMSOG protein-coupled estrogen receptorMAPKDulbecco's modified Eagle's mediumMTTSmall interfering RNAsiRNApolyacrylamide gel electrophoresisEndoxifenBrdUbicinchoninic acidTAMtamoxifenProliferationTris-buffered salineMelanomadithiothreitolDimethyl sulfoxidefetal bovine serumsulforhodamine BCytochrome P450enhanced chemifluorescenceAntiestrogensphosphoinositide-3-kinasephenylmethanesulphonyl fluoridelactate dehydrogenaseLDHPhosphate-buffered salineWestern blotProtein kinase Cmitogen activated protein kinaseextracellular signal-regulated kinasesEstrogen receptorInsulin-like growth factor-1 receptorG protein-coupled receptor 30G protein-coupled receptor
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Authors
Mariana P.C. Ribeiro, Armanda E. Santos, José B.A. Custódio,