title: Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC.
abstract: OBJECTIVE
  The effect of antioxidants on treatment of cancer is still controversial. Previously, we demonstrated that interaction of breast cancer cells with endothelial cells leads to tyrosine phosphorylation of VE-cadherin and disruption of endothelial adherens junction (EAJ). The molecular mechanism underlying the anti-metastatic effects of mushroom-derived active hexode correlated compound (AHCC) remains elusive.
  
  
  METHODS
  Several cellular and biochemical techniques were used to determine the contribution of oxidative stress in the disruption of EAJ and to test this hypothesis that AHCC inhibits the breast cancer cell-induced disruption of EAJ.
  
  
  RESULTS
  Interaction of breast cancer cells (MDA-MB-231 cells) with human umbilical vein endothelial cells (HUVECs) leads to an increase in generation of reactive oxygen species (ROS). Treatment of HUVECs with H2O2 or phorbol myristate acetate (PMA) led to tyrosine phosphorylation of VE-cadherin, dissociation of β-catenin from VE-cadherin complex and increased transendothelial migration (TEM) of MDA-MB-231 cells. Induction of VE-cadherin tyrosine phosphorylation by PMA or by interaction of MDA-MB-231 cells with HUVECs was mediated by HRas and protein kinase C-α signaling pathways. Disruption of EAJ and phosphorylation of VE-cadherin induced by interaction of MDA-MB-231 cells with HUVECs were attenuated when HUVECs were pretreated with an antioxidant, N-acetylcysteine (NAC) or AHCC. AHCC inhibited TEM of MDA-MB-231 cells and generation of ROS induced by interaction of MDA-MB-231 cells with HUVECs.
  
  
  CONCLUSIONS
  Our studies suggest that ROS contributes to disruption of EAJ induced by interaction of MDA-MB-231 cells with HUVECs and AHCC attenuates this alteration.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Health Science Center at Houston, USA; Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, USA. Electronic address: Mehran.Haidari@uth.tmc.edu.
authors.forename: Mehran
authors.initials: M
authors.lastname: Haidari
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Koji
authors.initials: K
authors.lastname: Wakame
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D022005:Adherens Junctions / Q000187:drug effects*; D015703:Antigens, CD / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010936:Plant Extracts / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000111:Acetylcysteine; D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D015820:Cadherins; D006861:Hydrogen Peroxide; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D013755:Tetradecanoylphorbol Acetate; D014443:Tyrosine; D051176:beta Catenin; D000099152:Cadherin 5
keywords: Active hexose correlated compound (AHCC); Adherens junction; Breast cancer cells; Reactive oxygen species; VE-cadherin