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Small change – big consequence: The impact of C15-C16 double bond in a D‑ring of estrone on estrogen receptor activity
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SYSNO ASEP 0575940 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Small change – big consequence: The impact of C15-C16 double bond in a D‑ring of estrone on estrogen receptor activity Author(s) Voňka, Petr (UEB-Q) ORCID
Rárová, L. (CZ)
Bazgier, V. (CZ)
Tichý, V. (CZ)
Kolářová, T. (CZ)
Holčáková, J. (CZ)
Berka, K. (CZ)
Kvasnica, Miroslav (UEB-Q) RID, ORCID
Oklešťková, Jana (UEB-Q) RID, ORCID, SAI
Kudová, Eva (UOCHB-X) RID, ORCID
Strnad, Miroslav (UEB-Q) RID, ORCID
Hrstka, Roman (UEB-Q) ORCIDNumber of authors 12 Article number 106365 Source Title Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier - ISSN 0960-0760
Roč. 233, OCT (2023)Number of pages 13 s. Language eng - English Country GB - United Kingdom Keywords Apoptosis ; Docking of steroid library ; Estrogen receptor alpha ; Luciferase assay ; Mitochondrial membrane potential OECD category Biochemistry and molecular biology R&D Projects LM2023055 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure e-INFRA CZ - 90140 - CESNET, zájmové sdružení právnických osob
BBMRI.cz IV - 90233 - Masarykův onkologický ústavMethod of publishing Open access Institutional support UEB-Q - RVO:61389030 ; UOCHB-X - RVO:61388963 UT WOS 001048999000001 EID SCOPUS 85165571434 DOI 10.1016/j.jsbmb.2023.106365 Annotation Estrogen receptor alpha (ER) is a key biomarker for breast cancer, and the presence or absence of ER in breast and other hormone-dependent cancers decides treatment regimens and patient prognosis. ER is activated after ligand binding typically by steroid. 2682 steroid compounds were used in a molecular docking study to identify novel ligands for ER and to predict compounds that may show anticancer activity. The effect of the most promising compounds was determined by a novel luciferase reporter assay. Two compounds, 7 and 12, showing ER inhibitory activity comparable to clinical inhibitors such as tamoxifen or fulvestrant were selected. We propose that the inhibitory effect of compounds 7 and 12 on ER is related to the presence of a double bond in their D-ring, which may protect against ER activation by reducing the electron density of the keto group, or may undergo metabolism leading to an active compound. Western blotting revealed that compound 12 decreased the level of ER in the breast cancer cell line MCF7, which was associated with reduced expression of both isoforms of the progesterone receptor, a well-known downstream target of ER. However, compound 12 has a different mechanism of action from fulvestrant. Furthermore, we found that compound 12 interferes with mitochondrial functions, probably by disrupting the electron transport chain, leading to induction of the intrinsic apoptotic pathway even in ER-negative breast cancer cells. In conclusion, the combination of computational and experimental methods shown here represents a rapid approach to determine the activity of compounds towards ER. Our data will not only contribute to research focused on the regulation of ER activity but may also be useful for the further development of novel steroid receptor-targeted drugs applicable in clinical practice. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2024 Electronic address https://doi.org/10.1016/j.jsbmb.2023.106365
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