Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-α-dependent gene expression.
Mol Nutr Food Res. 2016 Jun 25. Epub 2016 Jun 25. PMID: 27342949
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 (BRBs) are a promising approach to preventing endometrial cancer.
METHODS AND RESULTS: We examined 17 BRB constituents and metabolites (10μM or 10μg/ml, 48h) 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 estrogen receptor-positive endometrial cancer cells. UA enhanced the expression of ERβ, PGR, pS2, GREB1 while inhibiting the expression of ERα and GRIP1. Co-incubating 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. This article is protected by copyright. All rights reserved.