Adenovirus-mediated p14ARF gene transfer cooperates with Ad5CMV-p53 to induce apoptosis in human cancer cells

Yasuhisa Tango, Toshiyoshi Fujiwara, Takahiro Itoshima, Yoshiko Takata, Kou Katsuda, Futoshi Uno, Shoichiro Ohtani, Tohru Tani, Jack A. Roth, Noriaki Tanaka

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23 Citations (Scopus)

Abstract

p14ARF, a product of theINK4A/ARF locus, induces p53 upregulation by neutralizing the effects of MDM2, a transcriptional target of p53 that antagonizes its function. Here we report that adenovirus-mediated p14ARF gene transfer leads to the accumulation of ectopically transduced p53 and to apoptosis in human cancer cells. We constructed an adenoviral vector expressing p14ARF (Ad-ARF) and examined its synergistic effect with p53-expressing adenovirus (Ad5CMV-p53 or Ad-p53) in human lung and esophageal cancer cells. Simultaneous Ad-ARF and Ad-p53 infection increased p53 protein levels not only in a wild-type p53-expressing cell line, but also in cell lines with deleted p53. This resulted in a significant in vitro cytotoxicity compared with Ad-p53 infection alone. Coinfection of Ad-ARF and Ad-p53 also resulted in an increase in expression of p53-inducible genes, including p21WAF-1/Cip1, p53R2, and Noxa. In addition, the growth of human lung cancer tumors subcutaneously implanted into nu/nu mice was inhibited significantly by intratumoral injection with Ad-ARF and Ad-p53. Our data demonstrate that overexpression of ectopic p14ARF may render cells more sensitive to p53-mediated apoptosis, an outcome that has important implications for the treatment of human cancers.

Original languageEnglish
Pages (from-to)1373-1382
Number of pages10
JournalHuman Gene Therapy
Volume13
Issue number11
DOIs
Publication statusPublished - Jul 20 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Tango, Y., Fujiwara, T., Itoshima, T., Takata, Y., Katsuda, K., Uno, F., Ohtani, S., Tani, T., Roth, J. A., & Tanaka, N. (2002). Adenovirus-mediated p14ARF gene transfer cooperates with Ad5CMV-p53 to induce apoptosis in human cancer cells. Human Gene Therapy, 13(11), 1373-1382. https://doi.org/10.1089/104303402760128595