title: Genistein Suppresses Growth of Human Uterine Sarcoma Cell Lines via Multiple Mechanisms.
abstract: BACKGROUND
  The estrogen-like soy isoflavone genistein can suppress the growth of a number of different types of cancer cells, but its effect on uterine sarcoma is unknown.
  
  
  METHODS
  The impact of genistein on the proliferation of three uterine sarcoma cell lines, MES-SA, MES-SA-Dx5 and SK-UT-1, was evaluated. TOPflash luciferase reporter assay and western blotting were used to assess the influence of genistein on cellular signaling; DNA fragmentation was assessed as a measure of genistein-induced apoptosis.
  
  
  RESULTS
  Genistein inhibited the proliferation of all three cell lines, with half-maximal inhibitory concentrations of 19.2 μM, 13.1 μM and 9.3 μM for SK-UT-1, MES-SA-Dx5, and MES-SA, respectively. This inhibitory activity was accompanied by induction of DNA fragmentation at 48 h. Western blot analyses revealed three major expression patterns: induction of p53 and Dickkopf-related protein 1 (DKK1) and suppression of histone deacetylase 4/5/7 (HDAC4/5/7), dishevelled protein (DVL), BAX, survivin and phosphorylated mitogen-activated protein kinase kinase (phospho-MEK) in all three lines; suppression of p27 and β-catenin in the more resistant lines MES-SA-Dx5 and SK-UT-1; and suppression of Protein kinase B (AKT) and extracellular signal-regulated kinases (ERKs) phosphorylation and activation of caspase-3 in the parental derived lines MES-SA and MES-SA-Dx5. Down-regulation of β-catenin expression also coincided with decreases in TOPflash activity.
  
  
  CONCLUSIONS
  Genistein reduces sarcoma cell numbers through inhibition of proliferative signaling and through induction of programmed or non-programmed cell death. Genistein-mediated signaling changes were unique in each individual cell line, and the differential signaling responses in these three cell lines may contribute to their different levels of susceptibility to this compound.
authors.affiliation: Translational Research Laboratory, University of California San Francisco, San Francisco, CA, U.S.A.
authors.forename: Che-Chung
authors.initials: CC
authors.lastname: Yeh
authors.affiliation: Translational Research Laboratory, University of California San Francisco, San Francisco, CA, U.S.A.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Translational Research Laboratory, University of California San Francisco, San Francisco, CA, U.S.A.
authors.forename: Long
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, U.S.A.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Yang
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, U.S.A.
authors.forename: Biao
authors.initials: B
authors.lastname: He
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, U.S.A.
authors.forename: Liang
authors.initials: L
authors.lastname: You
authors.affiliation: Translational Research Laboratory, University of California San Francisco, San Francisco, CA, U.S.A. Michael.Mann@ucsfmedctr.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Mann
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000008:administration & dosage* / Q000737:chemistry; D006655:Histone Deacetylases / Q000096:biosynthesis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007529:Isoflavones / Q000008:administration & dosage / Q000737:chemistry; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013025:Glycine max / Q000737:chemistry; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D007529:Isoflavones; D019833:Genistein; D006655:Histone Deacetylases
keywords: Genistein; hormonal therapy; isoflavones; programmed cell death; sarcoma