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Suppression of tumor growth using a recombinant adenoviral vector carrying the dominant-negative mutant gene Survivin-D53A in a nude mice model

Cancer Gene Therapy volume 13, pages 762–770 (2006)Cite this article

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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Author notes

  1. D-E Zhu and N Höti: These two authors contributed equally to this work.

Authors and Affiliations

  1. 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

    D-E Zhu, N Höti, Z Song, L Jin & M Wu

  2. James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    N Höti

  3. Department of Pathology, Anhui Medical University, Hefei, Anhui, People's Republic of China

    Z Wu & Q Wu

  4. School of Biological Sciences, Nanyang Technological University, Singapore

    M Wu

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  1. D-E Zhu
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Correspondence to M Wu.

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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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