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Mol Nutr Food Res. 2016 Nov;60(11):2387-2395. doi: 10.1002/mnfr.201600048. Epub 2016 Jul 25.

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

Author information

1
School of Medicine and life Science, University of Jinan-Shandong Academy of Medical Science, Jinan, Shandong, China.
2
Department of Gynecology Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.
3
Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA.
4
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.
5
Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
6
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Abstract

SCOPE:

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.

METHODS AND RESULTS:

We examined 17 black raspberry constituents and metabolites (10 μM or 10 μg/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-α (ERα) dependent gene expression in ER-positive endometrial cancer cells. UA enhanced the expression of ERβ, PGR, pS2, GREB1 while inhibiting the expression of ERα and GRIP1. Coincubating UA-treated cells with the estrogen antagonist ICI182,780 abolished UA's estrogenic effects. Knocking down ERα suppressed PGR, pS2, and GREB gene expression but increased GRIP1 expression. Thus, UA's actions appear to be mediated through ERα.

CONCLUSION:

This study suggests that UA modulates ERα-dependent gene expression, thereby inhibiting endometrial cancer proliferation.

KEYWORDS:

Black raspberry; Cell proliferation; Endometrial cancer; Estrogen receptor; Urolithin A

PMID:
27342949
PMCID:
PMC5144574
DOI:
10.1002/mnfr.201600048
[Indexed for MEDLINE]
Free PMC Article

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