Suppression of tumor growth using a recombinant adenoviral vector carrying the dominant-negative mutant gene Survivin-D53A in a nude mice model.
Survivin (SVV), an inhibitor of apoptosis protein, is found to be upregulated in many cancers. We previously demonstrated that a dominant-negative mutant SVV-D53A was able to induce apoptosis in a p53-independent manner. Here, we report the construction and characterization of a recombinant replication-deficient adenoviral vector encoding a human SVV-D53A gene for its effectiveness against tumor growth both in vitro and in vivo. Transfection of liver tumor cells QGY-7703 with Ad-SVV-D53A results in significant apoptosis as measured by an increase in sub-G1 DNA content, procaspase-9 activation and further downstream PARP-1 cleavage. Furthermore, animal studies using QGY-7703 liver carcinoma xenografts in nude mice revealed that treatment of QGY-7703 cells with dominant-negative SVV-D53A, but not with wild-type SVV-adenovirus, prevents tumor outgrowth, inhibits growth of established tumors and results in a notably improved survival advantages in xenograft studies. Both the transferase-mediated dUTP nick-end labeling assay and immunostaining experiment demonstrated that tumor growth inhibition is associated with apoptosis induced by SVV-D53A expression. Taken together, these data suggest that recombinant adenovirus Ad-SVV-D53A carrying a Survivin dominant-negative gene SVV-D53A promotes apoptosis-mediated tumor suppression and could potentially be a promising candidate for cancer therapies.
Zhu
D-E
DE
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
Höti
N
N
Song
Z
Z
Jin
L
L
Wu
Z
Z
Wu
Q
Q
Wu
M
M
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000517:prevention & control; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007263:Infusions, Parenteral; D051034:Inhibitor of Apoptosis Proteins; D015552:Injections, Intralesional; D008113:Liver Neoplasms / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D000077022:Survivin; D014161:Transduction, Genetic; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin