title: Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-α-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 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.
  
  
  
  This study suggests that UA modulates ERα-dependent gene expression, thereby inhibiting endometrial cancer proliferation.
authors.affiliation: School of Medicine and life Science, University of Jinan-Shandong Academy of Medical Science, Jinan, Shandong, China.|Department of Gynecology Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Jo-Hsin
authors.initials: JH
authors.lastname: Chen
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Aguilera-Barrantes
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: Department of Gynecology Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.
authors.forename: Xiugui
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Li-Shu
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Stoner
authors.affiliation: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Huang
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D016889:Endometrial Neoplasms / Q000178:diet therapy / Q000235:genetics / Q000517:prevention & control; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D065856:Rubus / Q000737:chemistry* / Q000378:metabolism
chemical_list: D003374:Coumarins; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; C026423:3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one
keywords: Black raspberry; Cell proliferation; Endometrial cancer; Estrogen receptor; Urolithin A