title: Vitamin D3 Inhibits Wnt/β-Catenin and mTOR Signaling Pathways in Human Uterine Fibroid Cells.
abstract: Somatic mutations in the Med12 gene are known to activate Wnt/β-catenin signaling in human uterine fibroids (UFs).
  
  
  
  The objective of the study was to examine the role of vitamin D3 in the modulation of Wnt/β-catenin and mammalian target of rapamycin (mTOR) signaling in human UF cells.
  
  
  
  Immortalized human UF cells (HuLM) and human primary UF (PUF) cells were treated with increasing concentrations of vitamin D3 and thereafter analyzed using Western blots and immunocytochemistry.
  
  
  
  Wnt/β-catenin and mTOR signaling proteins in cultured HuLM and PUF cells were measured.
  
  
  
  UF tumors with Med12 somatic mutations showed an up-regulation of Wnt4 and β-catenin as compared with adjacent myometrium. Vitamin D3 administration reduced the levels of Wnt4 and β-catenin in both HuLM and PUF cells. Vitamin D3 also reduced the expression/activation of mTOR signaling in both cell types. In contrast, vitamin D3 induced the expression of DNA damaged-induced transcription 4 (an inhibitor of mTOR) and tuberous sclerosis genes (TSC1/2) in a concentration-dependent manner in HuLM cells. Furthermore, we observed a concentration-dependent reduction of Wisp1 (Wnt induced signaling protein 1) and flap endonuclease 1 proteins in HuLM cells. Additionally, abrogation of vitamin D receptor expression (by silencing) in normal myometrial cells induces Wnt4/β-catenin as well as prompts a fibrotic process including an increase in cell proliferation and increased extracellular matrix production. Together these results suggest that vitamin D3 functions as an inhibitor of Wnt4/β-catenin and mTOR signaling pathways, which may play major roles in fibroid pathogenesis.
  
  
  
  Vitamin D3 may have utility as a novel long-term therapeutic and/or preventive option for uterine fibroids.
authors.affiliation: Department of Obstetrics and Gynecology (A.A.-H., M.P.D., S.K.H.), Georgia Regents University, Medical College of Georgia, Augusta, Georgia 30912; and Department of Molecular Medicine (T.G.R.), Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900.
authors.forename: Ayman
authors.initials: A
authors.lastname: Al-Hendy
authors.affiliation: Department of Obstetrics and Gynecology (A.A.-H., M.P.D., S.K.H.), Georgia Regents University, Medical College of Georgia, Augusta, Georgia 30912; and Department of Molecular Medicine (T.G.R.), Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Diamond
authors.affiliation: Department of Obstetrics and Gynecology (A.A.-H., M.P.D., S.K.H.), Georgia Regents University, Medical College of Georgia, Augusta, Georgia 30912; and Department of Molecular Medicine (T.G.R.), Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Boyer
authors.affiliation: Department of Obstetrics and Gynecology (A.A.-H., M.P.D., S.K.H.), Georgia Regents University, Medical College of Georgia, Augusta, Georgia 30912; and Department of Molecular Medicine (T.G.R.), Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Halder
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D002762:Cholecalciferol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
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