Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC

• Published in: Life sciences (1973) 2013-12, Vol.93 (25-26), p.994-1003
• Main Authors: Haidari, Mehran, Zhang, Wei, Wakame, Koji
• Format: Article
• Language: English
• Subjects: acetylcysteine; Acetylcysteine - pharmacology; Active hexose correlated compound (AHCC); Adherens junction; Adherens Junctions - drug effects; Antigens, CD - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; antioxidants; Antioxidants - pharmacology; beta Catenin - metabolism; Breast cancer cells; breast neoplasms; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cadherins - metabolism; Cell Movement - drug effects; dissociation; Endothelial Cells - drug effects; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Female; Human Umbilical Vein Endothelial Cells; Humans; hydrogen peroxide; Hydrogen Peroxide - pharmacology; Male; neoplasm cells; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; oxidative stress; phosphorylation; Plant Extracts - pharmacology; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; protein kinase C; Reactive oxygen species; Reactive Oxygen Species - metabolism; signal transduction; Signal Transduction - drug effects; Tetradecanoylphorbol Acetate - pharmacology; transmission electron microscopy; Tumor Cells, Cultured; tyrosine; Tyrosine - metabolism; VE-cadherin
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2013.10.027

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. 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. 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. 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.