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

• Published in: Human gene therapy Vol. 13; no. 11; p. 1373
• Main Authors: Tango, Yasuhisa, Fujiwara, Toshiyoshi, Itoshima, Takahiro, Takata, Yoshiko, Katsuda, Kou, Uno, Futoshi, Ohtani, Shoichiro, Tani, Tohru, Roth, Jack A, Tanaka, Noriaki
• Format: Journal Article
• Language: English
• Published: United States 20-07-2002
• Subjects: Adenoviridae - genetics; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line; Cell Transformation, Viral; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Female; Gene Expression; Genes, p53 - genetics; Genetic Vectors; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Mice; Mice, Mutant Strains; Neoplasms, Experimental - therapy; Transduction, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p14ARF - genetics; Tumor Suppressor Protein p53 - genetics
• ISSN: 1043-0342

p14(ARF), a product of the INK4A/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 p14(ARF) gene transfer leads to the accumulation of ectopically transduced p53 and to apoptosis in human cancer cells. We constructed an adenoviral vector expressing p14(ARF) (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 p21(WAF-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 p14(ARF) may render cells more sensitive to p53-mediated apoptosis, an outcome that has important implications for the treatment of human cancers.