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Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-?-dependent gene expression.

ABSTRACT: Obese and overweight women are at high risk of developing endometrial cancer; indeed, many of endometrial cancer patients are obese. The increased number and size of adipocytes due to obesity elevate levels of circulating estrogens that stimulate cell proliferation in the endometrium. However, black raspberries are a promising approach to preventing endometrial cancer.We examined 17 black raspberry constituents and metabolites (10 ?M or 10 ?g/mL, 48 h) for their ability to prevent endometrial cancer cells from proliferating. Urolithin A (UA) was most able to suppress proliferation in a time- and dose-dependent manner (p < 0.05). It arrested the G2/M phase of the cell cycle by upregulating cyclin-B1, cyclin-E2, p21, phospho-cdc2, and CDC25B. UA also acted as an estrogen agonist by modulating estrogen receptor-? (ER?) dependent gene expression in ER-positive endometrial cancer cells. UA enhanced the expression of ER?, PGR, pS2, GREB1 while inhibiting the expression of ER? and GRIP1. Coincubating UA-treated cells with the estrogen antagonist ICI182,780 abolished UA's estrogenic effects. Knocking down ER? suppressed PGR, pS2, and GREB gene expression but increased GRIP1 expression. Thus, UA's actions appear to be mediated through ER?.This study suggests that UA modulates ER?-dependent gene expression, thereby inhibiting endometrial cancer proliferation.

SUBMITTER: Zhang W

PROVIDER: S-EPMC5144574 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-α-dependent gene expression.

Zhang Wei W Chen Jo-Hsin JH Aguilera-Barrantes Irene I Shiau Chung-Wai CW Sheng Xiugui X Wang Li-Shu LS Stoner Gary D GD Huang Yi-Wen YW

Molecular nutrition & food research 20160725 11

<h4>Scope</h4>Obese and overweight women are at high risk of developing endometrial cancer; indeed, many of endometrial cancer patients are obese. The increased number and size of adipocytes due to obesity elevate levels of circulating estrogens that stimulate cell proliferation in the endometrium. However, black raspberries are a promising approach to preventing endometrial cancer.<h4>Methods and results</h4>We examined 17 black raspberry constituents and metabolites (10 μM or 10 μg/mL, 48 h) f ...[more]

PMID: 27342949

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Project description:BackgroundEstrogen receptor β (ERβ) has been repeatedly suggested to play important roles in hormone-dependent cancer like in tumors of the breast, ovary or prostate. In this study, we intended to further elucidate its role in endometrial cancer.MethodsFor this purpose, we knocked down ERβ expression in two endometrial cancer cell lines, the ERα-negative/ERβ-positive line HEC-1A and the ERα/β-positive cell line RL95/2, by means of siRNA transfection. Cell proliferation after transfection was assessed using the fluorescent CTB Assay (Promega). In order to elucidate possible molecular mechanisms which might underlie the effect on proliferation, we performed transcriptome analyses by means of human Affymetrix Human Gene Chip 2.0. Additionally, we treated the employed cell lines with different ERβ modulators to examine their effect on proliferation.ResultssiRNA-mediated knockdown of ERβ significantly increased proliferation of both endometrial cancer cell lines. In HEC-1A cells, proliferation was significantly increased 4, 5 and 6 days after transfection, with a maximum of about 1.7-fold (p < 0.05) on day 6. Endometrial RL95/2 cells with an ERβ knockdown exhibited a clearly enhanced proliferation on day 3 and days 4 to 8, when even 2.4-fold higher numbers of viable cells were detected (p < 0.01). Transcriptome analysis revealed that this was accompanied by increased expression of several genes being known to be upregulated in cancer, including proliferation-associated genes and oncogenes, and by repression of genes associated with differentiation, apoptosis or growth inhibition. Corroborating the observed knockdown effects, treatment with the ERβ antagonists PHTTP and (R, R) THC was also able to induce proliferation of both cell lines.ConclusionsOur data clearly support the putative role of ERβ as tumor suppressor in endometrium as previously suggested in studies on other tissues and encourage further studies to find out to what extent this molecule might be a potential therapy target in this cancer entity.

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Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-?-dependent gene expression.

Publications

Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-α-dependent gene expression.

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