Deciphering the Molecular Mechanisms Sustaining the Estrogenic Activity of the Two Major Dietary Compounds Zearalenone and Apigenin in ER-Positive Breast Cancer Cell Lines

Lecomte, Sylvain; Demay, Florence; Pham, Thu Ha; Moulis, Solenn; Efstathiou, Théo; Chalmel, Frédéric; Pakdel, Farzad

doi:10.3390/nu11020237

Cited by 23 publications

(17 citation statements)

References 53 publications

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“…Zearalenone (ZEA) is frequently found in human and animal diet through consumption of fungal contaminated cereal products such as wheat, corn, oats and rye products 4 . ZEA is a non-steroidal estrogenic mycotoxin due to its structural similarities with 17-β-estradiol and therefore exert estrogenic activity via estrogen receptors 5 . ZEA promoted breast and prostate cancer cell in vitro 5 , 6 ; and ZEA metabolites were elevated in breast cancer patient in a study in Tunisia compared to controls 7 .…”

Section: Introductionmentioning

confidence: 99%

Low dose of zearalenone elevated colon cancer cell growth through G protein-coupled estrogenic receptor

Lee

Turner

et al. 2021

Sci Rep

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Colon cancer is one of the leading causes of cancer death worldwide. It is widely believed that environmental factors contribute to colon cancer development. Zearalenone (ZEA) is non-steroidal estrogenic mycotoxin that is widely found in the human diet and animal feeds. Most cancer studies of ZEA focused on estrogen sensitive cancers, while few focused on other types, such as colon cancer; despite the gastrointestinal tract being the first barrier exposed to food contaminants. This study investigated the stimulatory effects of ZEA on colon cancer cell lines and their underlying molecular mechanisms. ZEA promoted anchorage independent cell growth and cell cycle progression through promoting G1-to-S phase transition. Proliferative marker, cyclin D1 and Ki67 were found to be upregulated upon ZEA treatment. G protein-coupled estrogenic receptor 1 (GPER) protein expression was promoted upon ZEA treatment suggesting the involvement of GPER. The growth promoting effect mediated through GPER were suppressed by its antagonist G15. ZEA were found to promote the downstream parallel pathway, MAPK signaling pathway and Hippo pathway effector YAP1. Altogether, our observations suggest a novel mechanism by which ZEA could promote cancer growth and provide a new perspective on the carcinogenicity of ZEA.

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Section: Introductionmentioning

confidence: 99%

Low dose of zearalenone elevated colon cancer cell growth through G protein-coupled estrogenic receptor

Lee

Turner

et al. 2021

Sci Rep

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“…This effect was already described in 1998 by Zou and Ing [50] in the endometrium of ewes exposed to E2, and it emphasizes the need to select suitable reference genes for each analysis of mRNA expression. Although our initial hypothesis on the activation of genes carrying ERE motifs upon ZEN exposure is not conclusive, activation of GREB1 containing ERE in its promoter was very recently demonstrated on MCF-7 cells treated with ZEN [51]. In this study, authors used chromatin immunoprecipitation to show that ZEN induced the recruitment of ERα DNA-binding at chromatin sites.…”

Section: Discussionmentioning

confidence: 95%

Biotransformation of the Mycotoxin Zearalenone to its Metabolites Hydrolyzed Zearalenone (HZEN) and Decarboxylated Hydrolyzed Zearalenone (DHZEN) Diminishes its Estrogenicity In Vitro and In Vivo

Fruhauf¹,

Novak²,

Nagl³

et al. 2019

Toxins

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Zearalenone (ZEN)-degrading enzymes are a promising strategy to counteract the negative effects of this mycotoxin in livestock. The reaction products of such enzymes need to be thoroughly characterized before technological application as a feed additive can be envisaged. Here, we evaluated the estrogenic activity of the metabolites hydrolyzed zearalenone (HZEN) and decarboxylated hydrolyzed zearalenone (DHZEN) formed by hydrolysis of ZEN by the zearalenone-lactonase Zhd101p. ZEN, HZEN, and DHZEN were tested in two in vitro models, the MCF-7 cell proliferation assay (0.01–500 nM) and an estrogen-sensitive yeast bioassay (1–10,000 nM). In addition, we compared the impact of dietary ZEN (4.58 mg/kg) and equimolar dietary concentrations of HZEN and DHZEN on reproductive tract morphology as well as uterine mRNA and microRNA expression in female piglets (n = 6, four weeks exposure). While ZEN increased cell proliferation and reporter gene transcription, neither HZEN nor DHZEN elicited an estrogenic response, suggesting that these metabolites are at least 50–10,000 times less estrogenic than ZEN in vitro. In piglets, HZEN and DHZEN did not increase vulva size or uterus weight. Moreover, RNA transcripts altered upon ZEN treatment (EBAG9, miR-135a-5p, miR-187-3p and miR-204-5p) were unaffected by HZEN and DHZEN. Our study shows that both metabolites exhibit markedly reduced estrogenicity in vitro and in vivo, and thus provides an important basis for further evaluation of ZEN-degrading enzymes.

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“…no. ST579; Beyotime Institute of Biotechnology) (42). The results were determined using a flow cytometer (CytoFLEX; Beckman Coulter, Inc.).…”

Section: Methodsmentioning

confidence: 99%

Critical roles of Rad54 in tolerance to apigenin‑induced Top1‑mediated DNA damage

Zhao

et al. 2021

Exp Ther Med

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Apigenin (APG), a flavone sub-class of flavonoids, possesses a diverse range of biological activities, including anti-cancer and anti-inflammatory effects. Previous studies identified the genotoxicity of APG in certain cancer cells, which may be associated with its anticancer effect. However, the DNA damage repair mechanism induced by APG has remained elusive. In order to clarify the molecular mechanisms, the present study determined the toxicity of APG to the wild-type (WT) DT40 chicken B-lymphocyte cell line, as well as to DT40 cells with deletions in various DNA repair genes, and their sensitivities were compared. It was demonstrated that cells deficient of Rad54, a critical homologous recombination gene, were particularly sensitive to APG. Cell-cycle analysis demonstrated that APG caused an increase in the G 2 /M-phase population of Rad54-/cells that was greater than that in WT cells. Furthermore, it was demonstrated by immunofluorescence assay that Rad54-/cells exhibited significantly increased numbers of γ-phosphorylated H2AX variant histone foci and chromosomal aberrations compared to the WT cells in response to APG. Of note, the in vitro complex of enzyme assay indicated that APG induced increased topoisomerase I (Top1) covalent protein DNA complex in Rad54-/cells compared to WT cells. Finally, these results were verified using the TK6 human lymphoblastoid cell line and it was demonstrated that, as for DT40 cells, Rad54 deficiency sensitized TK6 cells to APG. The present study demonstrated that Rad54 was involved in the repair of APG-induced DNA damage, which was associated with Top1 inhibition.

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Deciphering the Molecular Mechanisms Sustaining the Estrogenic Activity of the Two Major Dietary Compounds Zearalenone and Apigenin in ER-Positive Breast Cancer Cell Lines

Cited by 23 publications

References 53 publications

Low dose of zearalenone elevated colon cancer cell growth through G protein-coupled estrogenic receptor

Low dose of zearalenone elevated colon cancer cell growth through G protein-coupled estrogenic receptor

Biotransformation of the Mycotoxin Zearalenone to its Metabolites Hydrolyzed Zearalenone (HZEN) and Decarboxylated Hydrolyzed Zearalenone (DHZEN) Diminishes its Estrogenicity In Vitro and In Vivo

Critical roles of Rad54 in tolerance to apigenin‑induced Top1‑mediated DNA damage

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