Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells

Markus D. Sachs, Meera Ramamurthy, Henk Van Der Poel, Thomas J. Wickham, Martine Lamfers, Winald Gerritsen, Wasim Chowdhury, Ying Li, Mark P. Schoenberg, Ronald Rodriguez

Research output: Contribution to journalArticle

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)477-486
Number of pages10
JournalCancer Gene Therapy
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2004
Externally publishedYes

Keywords

  • Adenoviral gene therapy
  • Bladder cancer
  • Coxsackie adenovirus receptor
  • Receptor upregulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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    Sachs, M. D., Ramamurthy, M., Van Der Poel, H., Wickham, T. J., Lamfers, M., Gerritsen, W., Chowdhury, W., Li, Y., Schoenberg, M. P., & Rodriguez, R. (2004). Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells. Cancer Gene Therapy, 11(7), 477-486. https://doi.org/10.1038/sj.cgt.7700726