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Ribozyme-mediated inhibition of survivin expression increases spontaneous and drug-induced apoptosis and decreases the tumorigenic potential of human prostate cancer cells

Oncogene volume 23, pages 386–394 (2004)Cite this article

Abstract

Survivin is a member of the inhibitor of apoptosis protein (IAP) family, which has been implicated in inhibition of apoptosis and control of mitotic progression. The finding that survivin is overexpressed in most human tumors but absent in normal adult tissues has led to the proposal of survivin as a promising therapeutic target for anticancer therapies. We decided to evaluate the effects of a ribozyme-based strategy for survivin inhibition in androgen-independent human prostate cancer cells. We constructed a Moloney-based retroviral vector expressing a ribozyme targeting the 3′ end of the CUA110 triplet in survivin mRNA, encoded as a chimeric RNA within adenoviral VA1 RNA. Polyclonal cell populations obtained by infection with the retroviral vector of two androgen-independent human prostate cancer cell lines (DU145 and PC-3) were selected for the study. Ribozyme-expressing prostate cancer cells were characterized by a significant reduction of survivin expression compared to parental cells transduced with a control ribozyme; the cells became polyploid, underwent caspase-9-dependent apoptosis and showed an altered pattern of gene expression, as detected by oligonucleotide array analysis. Survivin inhibition also increased the susceptibility of prostate cancer cells to cisplatin-induced apoptosis and prevented tumor formation when cells were xenografted in athymic nude mice. These findings suggest that manipulation of the antiapoptotic survivin pathway may provide a novel approach for the treatment of androgen-independent prostate cancer.

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Acknowledgements

This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro, the Italian Ministry of Health (R.F. 02/171 and R.F. 02/184) and the Consiglio Nazionale delle Ricerche (Special Project ‘Oncology’). MP was supported by a fellowship by FIRC.

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Authors and Affiliations

  1. Dipartimento di Oncologia Sperimentale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, 20133, Italy

    Marzia Pennati, Mara Binda, Gennaro Colella, Marco Folini, Sara Vignati, Alessandra Valentini, Michelandrea De Cesare, Graziella Pratesi, Maria Grazia Daidone & Nadia Zaffaroni

  2. Istituto di Fisiologia Clinica-CNR, Pisa, Italy

    Monica Zoppe' & Lorenzo Citti

  3. International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

    Mauro Giacca

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  1. Marzia Pennati
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Correspondence to Nadia Zaffaroni.

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Pennati, M., Binda, M., Colella, G. et al. Ribozyme-mediated inhibition of survivin expression increases spontaneous and drug-induced apoptosis and decreases the tumorigenic potential of human prostate cancer cells. Oncogene 23, 386–394 (2004). https://doi.org/10.1038/sj.onc.1207071

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