title: Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells.
abstract: Studies on bladder cancer cell lines have shown that low adenoviral (Ad) infectivity is associated with low-level coxsackie adenovirus receptor (CAR) expression. Recently, we and others demonstrated a tumor stage- and grade-dependent downregulation of CAR expression in a large series of clinical bladder cancer specimens. Here, we demonstrate adenoviral gene transfer can be markedly enhanced in bladder cancer cells by upregulation of CAR through the use of certain differentiating agents, including the histone deacetylase inhibitors (HDACI) trichostatin A and sodium phenylbutyrate. CAR upregulation to supraphysiologic levels was demonstrated by quantitative rt-PCR, Western blotting, flow cytometry and adenoviral gene transfer. Normal urothelial cells and CAR-positive papilloma cells (RT4) failed to demonstrate upregulation under the same conditions. Upregulation was cell cycle dependent, associated with increased adenoviral gene transfer and persisted for at least 7 days after a single treatment. Such upregulation, however, appears to be tumor cell specific, as other CAR-negative cell lines failed to demonstrate enhanced adenoviral gene transfer with the same treatments. These results provide a rational basis for combining HDACI therapy with gene therapy as a method of augmenting activity in bladder cancer, but this strategy may not be universally applicable to other cell types.
authors.affiliation: Brady Urological Institute, Johns Hopkins Hospital, Marburg 205, 600 N. Wolfe Street, Baltimore, Maryland 21287-2101, USA.
authors.forename: Markus D
authors.initials: MD
authors.lastname: Sachs
authors.forename: Meera
authors.initials: M
authors.lastname: Ramamurthy
authors.forename: Henk van der
authors.initials: Hv
authors.lastname: Poel
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wickham
authors.forename: Martine
authors.initials: M
authors.lastname: Lamfers
authors.forename: Winald
authors.initials: W
authors.lastname: Gerritsen
authors.forename: Wasim
authors.initials: W
authors.lastname: Chowdhury
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Mark P
authors.initials: MP
authors.lastname: Schoenberg
authors.forename: Ronald
authors.initials: R
authors.lastname: Rodriguez
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011991:Receptors, Virus; D006655:Histone Deacetylases