Abstract |
Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERβ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERβ expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re-expression by genetic engineering, as well as the use of targeted ERβ therapies, still constitute an important therapeutic approach. 3-{[2-chloro-1-(4-chlorobenzyl)-5-methoxy-6-methyl-1H-indol-3-yl]methylene}-5-hydroxy-6-methyl-1,3-dihydro-2H-indol-2-one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti-carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and liquid chromatography mass spectrometry were exploited to localize and quantify compound 3 in cells. Molecular docking was used to prove compound 3 binding to ERβ. Mass spectrometry-based approaches were used to analyze histone post-translational modifications. Finally, gene expression analyses revealed a set of genes regulated by the ERβ/3 complex, namely CCND1, MYC, CDKN2A, and ESR2, providing possible molecular mechanisms that underline the observed antiproliferative effects.
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Authors | Laura Verardi, Jessica Fiori, Vincenza Andrisano, Alessandra Locatelli, Rita Morigi, Marina Naldi, Carlo Bertucci, Elena Strocchi, Carla Boga, Gabriele Micheletti, Natalia Calonghi |
Journal | Molecules (Basel, Switzerland)
(Molecules)
Vol. 25
Issue 19
(Sep 27 2020)
ISSN: 1420-3049 [Electronic] Switzerland |
PMID | 32992652
(Publication Type: Journal Article)
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Chemical References |
- ESR2 protein, human
- Estrogen Receptor beta
- Indoles
- Neoplasm Proteins
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Topics |
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Estrogen Receptor beta
(agonists, chemistry, metabolism)
- Female
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Indoles
(chemistry, pharmacology)
- Molecular Docking Simulation
- Neoplasm Proteins
(agonists, chemistry, metabolism)
- Ovarian Neoplasms
(drug therapy, metabolism, pathology)
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