Abstract
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.
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Acknowledgements
We are grateful to Dr Ronald Rodriguez (Johns Hopkins University) for LNCAP and DU145 cell lines. This research was supported by a 973 grant (2002CB713702) from Ministry of Science and Technology of China; grants from the National Natural Science Foundation of China (30530200, 90208027, 30370308 and 30121001) and an ARC grant (to Wu Mian) from Ministry of Education, Singapore.
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Zhu, DE., Höti, N., Song, Z. et al. Suppression of tumor growth using a recombinant adenoviral vector carrying the dominant-negative mutant gene Survivin-D53A in a nude mice model. Cancer Gene Ther 13, 762–770 (2006). https://doi.org/10.1038/sj.cgt.7700952
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DOI: https://doi.org/10.1038/sj.cgt.7700952
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