Adenovirus-Mediated p14ARFGene Transfer Cooperates with Ad5CMV-p53 to Induce Apoptosis in Human Cancer Cells
| Autor: | Toshiyoshi Fujiwara, Kou Katsuda, Futoshi Uno, Noriaki Tanaka, Tohru Tani, Yoshiko Takata, Shoichiro Ohtani, Jack A. Roth, Yasuhisa Tango, Takahiro Itoshima |
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| Rok vydání: | 2002 |
| Předmět: |
Lung Neoplasms
Esophageal Neoplasms Genetic enhancement Genetic Vectors Gene Expression Apoptosis Biology medicine.disease_cause Adenoviridae Cell Line Viral vector Mice Downregulation and upregulation p14arf Transduction Genetic Carcinoma Non-Small-Cell Lung Tumor Suppressor Protein p14ARF Tumor Cells Cultured Genetics medicine Animals Humans Molecular Biology Genetic transfer Neoplasms Experimental Cell Transformation Viral Genes p53 Mice Mutant Strains Cell culture Carcinoma Squamous Cell Cancer research Molecular Medicine Female Tumor Suppressor Protein p53 |
| Zdroj: | Human Gene Therapy. 13:1373-1382 |
| ISSN: | 1557-7422 1043-0342 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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