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Enhanced tumor suppression in vitro and in vivo by co-expression of survivin-specific siRNA and wild-type p53 protein

Cancer Gene Therapy volume 17, pages 844–854 (2010)Cite this article

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Abstract

The development of malignant prostate cancer involves multiple genetic alterations. For example, alterations in both survivin and p53 are reported to have crucial roles in prostate cancer progression. However, little is known regarding the interrelationships between p53 and survivin in prostate cancer. Our data demonstrate that the expression of survivin is inversely correlated with that of wtp53 protein (rs=0.548) in prostate cancer and in normal prostate tissues. We have developed a therapeutic strategy, in which two antitumor factors, small interfering RNA-survivin and p53 protein, are co-expressed from the same plasmid, and have examined their effects on the growth of PC3, an androgen-independent prostate cancer cell line. When p53 was expressed along with a survivin-specific short hairpin RNA (shRNA), tumor cell proliferation was significantly suppressed and apoptosis occurred. In addition, this combination also abrogated the expression of downstream target molecules such as cyclin-dependent kinase 4 and c-Myc, while enhancing the expression of GRIM19. These changes in gene expression occurred distinctly in the presence of survivin-shRNA/wtp53 compared with control or single treatment groups. Intratumoral injection of the co-expressed construct inhibited the growth and survival of tumor xenografts in a nude mouse model. These studies revealed evidence of an interaction between p53 and survivin proteins plus a complex signaling network operating downstream of the wtp53-survivin pathway that actively controls tumor cell proliferation, survival and apoptosis.

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Acknowledgements

This work was supported by ‘The Research Fund for the Doctoral Program of Higher Education China’ in 2007. Grant 20070183012. We thank Dr Ruijuan Gao, Tyler Bassett and Suqin Pan for providing valuable help and technical support. DVK is supported by the NIH grants CA105005 and CA78282.

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Authors and Affiliations

  1. Department of Pathophysiology, Norman Bethune College of Medicine and Prostate Diseases Prevention and Treatment Research Center, Jilin University, Changchun, China

    Y Shao, Y Liu, C Shao, X Li, F Li, L Zhang, D Zhao, L Sun, X Zhao & Y Li

  2. Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, MD, USA

    J Hu

  3. Laboratory of Enteric and Sexually Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA

    D J Kopecko & D Q Xu

  4. Department of Microbiology and Immunology, Greene Baum Cancer Center, Molecular Biology Program, University of Maryland School of Medicine, Baltimore, MD, USA

    D V Kalvakolanu

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Correspondence to Y Li or D Q Xu.

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Shao, Y., Liu, Y., Shao, C. et al. Enhanced tumor suppression in vitro and in vivo by co-expression of survivin-specific siRNA and wild-type p53 protein. Cancer Gene Ther 17, 844–854 (2010). https://doi.org/10.1038/cgt.2010.41

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