Glyceollin I enantiomers distinctly regulate ER-mediated gene expression

Payton‐Stewart, Florastina; Khupse, Rahul; Boué, Stephen M.; Elliott, Steven; Zimmermann, Maria; Skripnikova, Elena; Ashe, Hasina; Tilghman, Syreeta L.; Beckman, Barbara S.; Cleveland, Thomas E.; McLachlan, John A.; Bhatnagar, Deepak; Wiese, Thomas E.; Erhardt, Paul; Burow, Matthew E.

doi:10.1016/j.steroids.2010.05.007

Cited by 30 publications

(32 citation statements)

References 50 publications

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“…This suggests that glyceollins do not act as conventional antiestrogens, such as tamoxifen, but rather act through both ER-dependent and ER-independent pathways, although the ER-dependent pathway seems to be predominant. Burow and collaborators reported that glyceollins could antagonize the E2-mediated stimulation of an ERE-luciferase reporter plasmid [11, 12, 15]. Although this was not observed in our study, the use of different ERE sequences and cell lines and differences in the duration of the treatment could account for this discrepancy.…”

Section: Discussioncontrasting

confidence: 69%

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Glyceollins trigger anti-proliferative effects through estradiol-dependent and independent pathways in breast cancer cells

et al. 2017

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BackgroundEstrogen receptors (ER) α and β are found in both women and men in many tissues, where they have different functions, including having roles in cell proliferation and differentiation of the reproductive tract. In addition to estradiol (E2), a natural hormone, numerous compounds are able to bind ERs and modulate their activities. Among these compounds, phytoestrogens such as isoflavones, which are found in plants, are promising therapeutics for several pathologies. Glyceollins are second metabolites of isoflavones that are mainly produced in soybean in response to an elicitor. They have potentially therapeutic actions in breast cancer by reducing the proliferation of cancer cells. However, the molecular mechanisms driving these effects remain elusive.MethodsFirst, to determine the proliferative or anti-proliferative effects of glyceollins, in vivo and in vitro approaches were used. The length of epithelial duct in mammary gland as well as uterotrophy after treatment by E2 and glyceollins and their effect on proliferation of different breast cell line were assessed. Secondly, the ability of glyceollin to activate ER was assessed by luciferase assay. Finally, to unravel molecular mechanisms involved by glyceollins, transcriptomic analysis was performed on MCF-7 breast cancer cells.ResultsIn this study, we show that synthetic versions of glyceollin I and II exert anti-proliferative effects in vivo in mouse mammary glands and in vitro in different ER-positive and ER-negative breast cell lines. Using transcriptomic analysis, we produce for the first time an integrated view of gene regulation in response to glyceollins and reveal that these phytochemicals act through at least two major pathways. One pathway involving FOXM1 and ERα is directly linked to proliferation. The other involves the HIF family and reveals that stress is a potential factor in the anti-proliferative effects of glyceollins due to its role in increasing the expression of REDD1, an mTORC1 inhibitor.ConclusionOverall, our study clearly shows that glyceollins exert anti-proliferative effects by reducing the expression of genes encoding cell cycle and mitosis-associated factors and biomarkers overexpressed in cancers and by increasing the expression of growth arrest-related genes. These results reinforce the therapeutic potential of glyceollins for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-017-0182-1) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 69%

“…Thus, chemically synthesized glyceollin I was generated and assessed. It was shown that the natural enantiomer exerted anti-proliferative activities against numerous cell lines, including ER-positive breast cancer cells [14], and that the compound is a potent inhibitor of ER activation [15]. …”

Section: Introductionmentioning

confidence: 99%

Glyceollins trigger anti-proliferative effects through estradiol-dependent and independent pathways in breast cancer cells

et al. 2017

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“…Thus, this study demonstrated that glyceollin I acts as a potent ERs antagonist (Zimmerman et al, 2006). Moreover, further studies attributed the antiestrogenic activity of glyceollin I to the natural (−)-glyceollin I enantiomer, which was compared to those of the racemate and of the unnatural (+) enantiomer (Payton-Stewart et al, 2010). Furthermore, Glyceollin I proved to reduce E 2 -stimulated proliferation of MCF7 cells and E 2 -stimulated breast and ovarian cancer in vitro , and in vivo reduced E 2 -stimulated breast and ovarian cancer and E 2 -induced uterus growth, in an ERs dependent manner (Salvo et al, 2012).…”

Section: Natural Xenoestrogensmentioning

confidence: 99%

Risks and benefits related to alimentary exposure to xenoestrogens

Paterni

Granchi

Minutolo

2017

Critical Reviews in Food Science and Nutrition

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Xenoestrogens are widely diffused in the environment and in food, thus a large portions of human population is worldwide exposed to them. Among alimentary xenoestrogens, phytoestrogens (PhyEs) are increasingly being consumed because of their potential health benefits, although there are also important risks associated to their ingestion. Furthermore, other xenoestrogens that may be present in food are represented by other chemicals possessing estrogenic activities, that are commonly defined as endocrine disrupting chemicals (EDCs). EDCs pose a serious health concern since they may cause a wide range of health problems, starting from pre-birth till adult lifelong exposure. We herein provide an overview of the main classes of xenoestrogens, which are classified on the basis of their origin, their structures and their occurrence in the food chain. Furthermore, their either beneficial or toxic effects on human health are discussed in this review.

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“…All of these results demonstrated that DES caused up-regulation of Fas or FasL expression by generating transcription factors and binding with cis-regulatory motifs present in Fas or FasL promoter regulated their expression. Payton-Stewart et al (2010) have shown ER-mediated gene expression through ERE cis-regulatory motif present in the promoter. They have demonstrated that glyceollin I enantiomers that bind with ER regulate several genes through the ERE of their promoter.…”

Section: Des Regulates Fas/fasl Via Ere and Nf-b 359mentioning

confidence: 99%

Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-κB Motifs

Singh

Nagarkatti

2012

J Pharmacol Exp Ther

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Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor B (NF-B), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-B, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-B2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions.

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Glyceollin I enantiomers distinctly regulate ER-mediated gene expression

Cited by 30 publications

References 50 publications

Glyceollins trigger anti-proliferative effects through estradiol-dependent and independent pathways in breast cancer cells

Glyceollins trigger anti-proliferative effects through estradiol-dependent and independent pathways in breast cancer cells

Risks and benefits related to alimentary exposure to xenoestrogens

Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-κB Motifs

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