Antiestrogenic activity of flavonoid phytochemicals mediated via the c-Jun N-terminal protein kinase pathway. Cell-type specific regulation of estrogen receptor alpha

Collins‐Burow, Bridgette M.; Antoon, James W.; Frigo, Daniel E.; Elliott, Steven; Weldon, Christopher B.; Boué, Stephen M.; Beckman, Barbara S.; Curiel, Tyler J.; Alam, Jawed; McLachlan, John A.; Burow, Matthew E.

doi:10.1016/j.jsbmb.2012.05.004

Cited by 20 publications

(11 citation statements)

References 65 publications

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“…Some of the flavonoids (e.g., genistein, biochanin A, apigenin) acted as antagonists in the ER-bla assay and as agonists in the BG1 ER-luc assay. This behavior may be explained by selective receptor modulator activity33. One aspect of nuclear receptor pharmacology that affects how compounds are assigned active agonist or active antagonist calls results from partial agonist behavior in the assays.…”

Section: Discussionmentioning

confidence: 99%

Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway

Huang

Sakamuru

Martin

et al. 2014

Sci Rep

152

156

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The U.S. Tox21 program has screened a library of approximately 10,000 (10K) environmental chemicals and drugs in three independent runs for estrogen receptor alpha (ERα) agonist and antagonist activity using two types of ER reporter gene cell lines, one with an endogenous full length ERα (ER-luc; BG1 cell line) and the other with a transfected partial receptor consisting of the ligand binding domain (ER-bla; ERα β-lactamase cell line), in a quantitative high-throughput screening (qHTS) format. The ability of the two assays to correctly identify ERα agonists and antagonists was evaluated using a set of 39 reference compounds with known ERα activity. Although both assays demonstrated adequate (i.e. >80%) predictivity, the ER-luc assay was more sensitive and the ER-bla assay more specific. The qHTS assay results were compared with results from previously published ERα binding assay data and showed >80% consistency. Actives identified from both the ER-bla and ER-luc assays were analyzed for structure-activity relationships (SARs) revealing known and potentially novel ERα active structure classes. The results demonstrate the feasibility of qHTS to identify environmental chemicals with the potential to interact with the ERα signaling pathway and the two different assay formats improve the confidence in correctly identifying these chemicals.

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Section: Discussionmentioning

confidence: 99%

Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway

Huang

Sakamuru

Martin

et al. 2014

Sci Rep

152

156

View full text Add to dashboard Cite

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“…Reporter gene assays were performed as previously described (49,50). MCF-7TN-R cells were plated at 50,000 cells per 24-well plate and allowed to attach overnight.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition

Antoon

Nitzchke

Martin

et al. 2013

International Journal of Oncology

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Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global miRNA gene expression profiling, we identified miRNA alterations associated with the development of death receptor resistance and EMT progression. We further investigated the role of p38 MAPK in this process, showing dose-dependent inactivation of p38 by its inhibitor RWJ67657 and decreased downstream ATF and NF-κB signaling. Pharmacological inhibition of p38 also decreased chemoresistant cancer tumor growth in xenograft animal models. Interestingly, inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT markers Twist, Snail, Slug and ZEB and protein and mRNA levels of Twist, a known EMT promoter, concomitant with decreased N-cadherin protein. RWJ67657 treatment also altered the expression of several miRNAs known to promote therapeutic resistance, including miR-200, miR-303, miR-302, miR-199 and miR-328. Taken together, our results demonstrate the roles of multiple microRNAs and p38 signaling in the progression of cancer and demonstrate the therapeutic potential of targeting the p38 MAPK pathway for reversing EMT in an advanced tumor phenotype.

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“…Meanwhile, accumulating evidence proves that some phytoestrogens exhibit antiestrogenic activity via ER-mediated signaling pathway [16,17,18]. For example, Nakamura et al reported that genistein, an isoflavone found in soy, inhibited proliferation and decreased invasive potential of human osteosarcoma cell line LM8, indicating the role of phytoestrogens in the prevention and treatment of osteosarcomas [19].…”

Section: Discussionmentioning

confidence: 99%

The Proapoptotic Effect of Formononetin in Human Osteosarcoma Cells: Involvement of Inactivation of ERK and Akt Pathways

Liu¹,

He²,

Chen³

et al. 2014

Cell Physiol Biochem

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Background: Previous studies have shown that some phytoestrogens inhibits proliferation and induces apoptosis in estrogen-dependent cancers via estrogen receptor (ER)-mediated signaling pathway. In view of the expression of ER in human osteosarcoma cells, the purpose of this study is to investigate whether formononetin and calycosin, two of the major isoflavones in Radix astragali, could also elicit anti-tumor activity against osteosarcoma, along with the underlying mechanism. Methods: Human osteosarcoma cells U2OS were respectively treated with various concentrations of formononetin or calycosin. Cell proliferation was determined by MTT assay, while apoptosis by flow cytometry. Next, the expression levels of apoptosis-related genes ERK, Akt, Bcl-2, Bax and caspase-3 were quantified by real-time PCR and Western blotting. Results: Formononetin exhibited higher anti-proliferative activities toward human osteosarcoma cells U2OS, when compared with calycosin. Therefore, U2OS cells were then respectively treated with various concentrations of formononetin, in order to elucidate the isoflavones-related signaling pathway. It was found that formononetin dose-dependently triggered apoptosis of U2OS cells in vitro. Furthermore, treatment of formononetin led to significant inactivation of ERK and Akt, followed by downregulation of Bcl-2, upregulation of Bax and finally increased expression of caspase-3. Conclusion: Formononetin is more effective than calycosin at promoting cell death of U2OS cells by induction of apoptosis, which is mediated by inactivation of ERK and Akt signaling pathways. Thus isoflavones, especially formononetin, may be useful as anti-cancer drugs for osteosarcoma through their apoptosis-inducing effects.

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Antiestrogenic activity of flavonoid phytochemicals mediated via the c-Jun N-terminal protein kinase pathway. Cell-type specific regulation of estrogen receptor alpha

Cited by 20 publications

References 65 publications

Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway

Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway

Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition

The Proapoptotic Effect of Formononetin in Human Osteosarcoma Cells: Involvement of Inactivation of ERK and Akt Pathways

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