Adenovirus-mediated p14ARF gene transfer cooperates with Ad5CMV-p53 to induce apoptosis in human cancer cells.
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.
Tango
Yasuhisa
Y
First Department of Surgery, Shiga University of Medical Science, Shiga 520-2192, Japan.
Fujiwara
Toshiyoshi
T
Itoshima
Takahiro
T
Takata
Yoshiko
Y
Katsuda
Kou
K
Uno
Futoshi
F
Ohtani
Shoichiro
S
Tani
Tohru
T
Roth
Jack A
JA
Tanaka
Noriaki
N
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002472:Cell Transformation, Viral; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D016158:Genes, p53 / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000628:therapy*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53