Small change – big consequence: The impact of C15-C16 double bond in a D‑ring of estrone on estrogen receptor activity

0575940 - ÚEB 2024 RIV GB eng J - Journal Article
Voňka, Petr - Rárová, L. - Bazgier, V. - Tichý, V. - Kolářová, T. - Holčáková, J. - Berka, K. - Kvasnica, Miroslav - Oklešťková, Jana - Kudová, Eva - Strnad, Miroslav - Hrstka, Roman
Small change – big consequence: The impact of C15-C16 double bond in a D‑ring of estrone on estrogen receptor activity.
Journal of Steroid Biochemistry and Molecular Biology. Roč. 233, OCT (2023), č. článku 106365. ISSN 0960-0760
R&D Projects: GA MŠMT(CZ) LM2023055; GA MŠMT LX22NPO5102
Research Infrastructure: e-INFRA CZ - 90140; BBMRI.cz IV - 90233
Institutional support: RVO:61389030 ; RVO:61388963
Keywords : Apoptosis * Docking of steroid library * Estrogen receptor alpha * Luciferase assay * Mitochondrial membrane potential
OECD category: Biochemistry and molecular biology
Impact factor: 4.1, year: 2022
Method of publishing: Open access
https://doi.org/10.1016/j.jsbmb.2023.106365

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.
Permanent Link: https://hdl.handle.net/11104/0345624