Wedelolactone induces growth of breast cancer cells by stimulation of estrogen receptor signalling.

Tereza Nehybova, Jan Smarda, Lukas Daniel, Jan Brezovsky, Petr Benes

Journal: The Journal of steroid biochemistry and molecular biology 2015;152():76-83

PMID: 25934092

Full Text on Elsevier Science View on PubMed

Abstract

Wedelolactone, a plant coumestan, was shown to act as anti-cancer agent for breast and prostate carcinomas in vitro and in vivo targeting multiple cellular proteins including androgen receptors, 5-lipoxygenase and topoisomerase IIα. It is cytotoxic to breast, prostate, pituitary and myeloma cancer cell lines in vitro at μM concentrations. In this study, however, a novel biological activity of nM dose of wedelolactone was demonstrated. Wedelolactone acts as agonist of estrogen receptors (ER) α and β as demonstrated by transactivation of estrogen response element (ERE) in cells transiently expressing either ERα or ERβ and by molecular docking of this coumestan into ligand binding pocket of both ERα and ERβ. In breast cancer cells, wedelolactone stimulates growth of estrogen receptor-positive cells, expression of estrogen-responsive genes and activates rapid non-genomic estrogen signalling. All these effects can be inhibited by pretreatment with pure ER antagonist ICI 182,780 and they are not observed in ER-negative breast cancer cells. We conclude that wedelolactone acts as phytoestrogen in breast cancer cells by stimulating ER genomic and non-genomic signalling pathways.

Address: Laboratory of Cellular Differentiation, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5/A36, 625 00 Brno, Czech Republic.; Laboratory of Cellular Differentiation, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5/A36, 625 00 Brno, Czech Republic; Masaryk Memorial Cancer Institute, RECAMO, Zluty kopec 7, 656 53 Brno, Czech Republic.; Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment RECETOX, Faculty of Science, Masaryk University, Kamenice 5/A13, 625 00 Brno, Czech Republic; International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne's University Hospital, Pekarska 53, 656 91 Brno, Czech Republic.; Laboratory of Cellular Differentiation, Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5/A36, 625 00 Brno, Czech Republic; International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne's University Hospital, Pekarska 53, 656 91 Brno, Czech Republic. Electronic address: [email protected].

DOI: 10.1016/j.jsbmb.2015.04.019

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MeSH Terms: Antineoplastic Agents, Binding Sites, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Coumarins, Estradiol, Estrogen Receptor Antagonists, Estrogen Receptor alpha, Estrogen Receptor beta, Estrogens, Female, Fulvestrant, HEK293 Cells, Humans, MCF-7 Cells, Molecular Docking Simulation, Response Elements, Signal Transduction, Transcription Factor AP-1, Transcriptional Activation