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

Pennati, Marzia; Binda, Mara; Colella, Gennaro; Zoppé, Monica; Folini, Marco; Vignati, Sara; Valentini, Alessandra; Citti, Lorenzo; Cesare, Michelandrea De; Pratesi, Graziella; Giacca, Mauro; Daidone, Maria Grazia; Zaffaroni, Nadia

doi:10.1038/sj.onc.1207071

Cited by 88 publications

(53 citation statements)

References 30 publications

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“…Immunohistochemical, Western blot and RT-PCR analysis showed that Survivin was overexpressed both in human PCa DU145 cells and human primary PCa tissues. These data are consistent with other studies 5,8,15 that showed an abnormal activation of Survivin in PCa. The importance of GRIM-19 in tumor growth regulation has been realized recently.…”

Section: Discussionsupporting

confidence: 93%

“…This observation is in agreement with the fact that RNA interference does not completely block gene transcription, especially when the target mRNA is expressed at abnormally high levels. 14,15 In order to enhance the antitumor efficiency, we added a second anti-tumor gene associated with retinoid-interferon (IFN)-induced mortality , by constructing a co-expression plasmid.…”

Section: Introductionmentioning

confidence: 99%

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Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth

Liu

Zhang²,

Guo³

et al. 2012

Asian J Androl

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Persistent activation of Survivin and its overexpression contribute to the formation, progression and metastasis of several different tumor types. Therefore, Survivin is an ideal target for RNA interference mediated-growth inhibition. Blockade of Survivin using specific short hairpin RNAs (shRNA) can significantly reduce prostate tumor growth. RNA interference does not fully ablate target gene expression, owing to the idiosyncrasies associated with shRNAs and their targets. To enhance the therapeutic efficacy of Survivin-specific shRNA, we employed a combinatorial expression of Survivin-specific shRNA and gene associated with retinoid-interferon-induced mortality-19 (GRIM-19). Then, the GRIM-19 coding sequences and Survivin-specific shRNAs were used to create a dual expression plasmid vector and were carried by an attenuated strain of Salmonella enteric serovar typhimurium (S. typhimurium) to treat prostate cancer in vitro and in vivo. We found that the co-expressed Survivin-specific shRNA and GRIM-19 synergistically and more effectively inhibited prostate tumor proliferation and survival, when compared with treatment with either single agent alone in vitro and in vivo. This study has provided a novel cancer gene therapeutic approach for prostate cancer.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth

Liu

Zhang²,

Guo³

et al. 2012

Asian J Androl

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“…Targeting the loss or inactivation of survivin in cancer cells often results in spontaneous apoptosis and/ or enhanced apoptosis induced by chemotherapeutic agents (Altieri, 2003a). Notably, antagonizing survivin expression in DU-145 human prostate cancer cells by ribozyme increased their sensitivity to cisplatin-induced apoptosis (Pennati et al, 2004). We also observed similar results in NRP-154 cells treated with taxol.…”

Section: Discussionsupporting

confidence: 74%

Rb/E2F4 and Smad2/3 link survivin to TGF-β-induced apoptosis and tumor progression

et al. 2008

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Survivin is a prosurvival protein overexpressed in many cancers through mechanisms that remain poorly explored, and is implicated in control of tumor progression and resistance to cancer chemotherapeutics. Here, we report a critical role for survivin in the induction of apoptosis by transforming growth factor-b (TGF-b). We show that TGF-b rapidly downregulates survivin expression in prostate epithelial cells, through a unique mechanism of transcriptional suppression involving Smads 2 and 3, Rb/ E2F4, and the cell-cycle repressor elements CDE and CHR. This TGF-b response is triggered through a Smad2/3-dependent hypophosphorylation of Rb and the subsequent association of the Rb/E2F4 repressive complex to CDE/CHR elements in the proximal region of the survivin promoter. Viral-mediated gene delivery experiments, involving overexpressing or silencing survivin, reveal critical roles of survivin in apoptosis induced by TGF-b alone or in cooperation with cancer therapeutic agents. We propose a novel TGF-b/Rb/survivin axis with a putative role in the functional switch of TGF-b from tumor suppressor to tumor promoter.

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“…Overexpression of survivin is associated with a more aggressive disease, drug resistance, increased risk of recurrence and poor survival in cancer patients (Monzo et al, 1999;Swana et al, 1999;Adida et al, 2000;Kuwabara et al, 2001). Accordingly, inhibiting the expression of survivin can reduce tumor growth potential and result in an increased sensitivity to anticancer agents (Tu et al, 2003;Pennati et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

An alternatively spliced survivin variant is positively regulated by p53 and sensitizes leukemia cells to chemotherapy

Zhu

Findley

et al. 2004

Oncogene

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Survivin is a unique member of the inhibitor of apoptosis protein family, and its expression is regulated by p53. Recent identification of several functionally divergent survivin variants augments the complexity of survivin action as well as its regulation. Here we report that survivin-2B (retaining a part of intron 2 as a cryptic exon) is positively regulated by p53, and its overexpression plays a role in sensitizing leukemia cells to chemotherapeutic drug doxorubicin. Doxorubicin treatment activated p53, downregulated survivin and survivin-DEx3 but upregulated survivin-2B in EU-3, an acute lymphocytic leukemia (ALL) cell line with wild-type (wt)-p53 phenotype. In contrast, doxorubicin treatment failed to induce these alterations in EU-6 cells, a mutant-p53 ALL cell line. To specify the role of wt-p53 in regulating survivin and its variants, a temperature-sensitive p53 mutant plasmid p53-143 was transfected into EU-4, a p53-null ALL cell line, to establish a subline EU-4/p53-143. When EU-4/p53-143 cell culture was shifted from 37.5 C to the wt-p53-permissive temperature (32.5 C), the expression of survivin and survivin-DEx3 was decreased whereas survivin-2B expression was increased, confirming the distinct regulatory effect of p53 on survivin and its variants. To clarify the role of survivin-2B in the process of apoptosis, survivin-2B cDNA was cloned into pcDNA3HA vector and transfected into EU-4 cells. Enforced expression of survivin-2B in EU-4 cells inhibited cell growth and sensitized these cells to doxorubicin-induced apoptosis. These results suggest that survivin-2B variant is a proapoptotic factor and its expression is upregulated by p53.

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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

Cited by 88 publications

References 30 publications

Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth

Plasmid-based Survivin shRNA and GRIM-19 carried by attenuated Salmonella suppresses tumor cell growth

Rb/E2F4 and Smad2/3 link survivin to TGF-β-induced apoptosis and tumor progression

An alternatively spliced survivin variant is positively regulated by p53 and sensitizes leukemia cells to chemotherapy

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