title: HDAC inhibition suppresses bladder cancer cell adhesion to collagen under flow conditions.
abstract: The influence of the histone deacetylase (HDAC)-inhibitor, valproic acid (VPA), on bladder cancer cell adhesion in vitro was investigated in this paper. TCCSUP and RT-112 bladder cancer cells were treated with VPA (0.5 or 1 mM) twice or thrice weekly for 14 days. Controls remained untreated. Tumour cell interaction with immobilized collagen was evaluated by a flow-based adhesion assay using a shear force of 2 or 4 dyne/cm(2). The effects of VPA on the integrin adhesion receptors α3, α5, β1, β3 and β4 were assessed by flow cytometry to determine integrin surface expression and by western blotting to determine the cytoplasmic integrin level. VPA of 0.5 mM and 1 mM significantly prevented binding of both RT-112 and TCCSUP cells to collagen, compared with the untreated controls. Adhesion was reduced to a higher extent when RT-112 (subjected to 2 dyne/cm(2)) or TCCSUP (subjected to 2 or 4 dyne/cm(2)) tumour cells were treated with VPA three times a week, compared to the two times a week protocol. VPA caused a significant up-regulation of the integrin α3, α5, β1, β3 and β4 subtypes on the TCCSUP cell surface membrane. In RT-112 cells, only integrin α5 was elevated on the cell surface following VPA exposure. Western blotting revealed an up-regulation of α3, α5, β3 and β4 integrins and down-regulation of the integrin β1 protein by VPA in TCCSUP. VPA also up-regulated α5 and down-regulated β1 integrin in RT-112 cells, but also reduced α3 and β3 in TCCSUP. VPA exerted adhesion-blocking properties on bladder cancer cells under physiologic flow conditions. The effects were accompanied by distinct modifications of the integrin expression profile, which differ depending on the cell lines used. Application of VPA might be an innovative option to prevent bladder cancer dissemination.
authors.affiliation: Department of Urology, Johann Wolfgang Goethe-University, 60590 Frankfurt am Main, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Juengel
authors.forename: Sascha
authors.initials: S
authors.lastname: Meyer dos Santos
authors.forename: Tanja
authors.initials: T
authors.lastname: Schneider
authors.forename: Jasmina
authors.initials: J
authors.lastname: Makarevic
authors.forename: Lukasz
authors.initials: L
authors.lastname: Hudak
authors.forename: Georg
authors.initials: G
authors.lastname: Bartsch
authors.forename: Axel
authors.initials: A
authors.lastname: Haferkamp
authors.forename: Christoph
authors.initials: C
authors.lastname: Wiesner
authors.forename: Roman A
authors.initials: RA
authors.lastname: Blaheta
mesh_terms: D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism*; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D016023:Integrins; D014635:Valproic Acid; D003094:Collagen
keywords: Valproic acid; bladder carcinoma; cell adhesion; integrin receptors