Wei Zhang1,2, Jo-Hsin Chen3, Irene Aguilera-Barrantes4, Chung-Wai Shiau5, Xiugui Sheng2, Li-Shu Wang6, Gary D Stoner6, Yi-Wen Huang3. 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.
SCOPE: Obese and overweight women are at high risk of developing endometrial cancer; indeed, many of endometrial cancerpatients 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.
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