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Suppression of colorectal tumor growth by regulated survivin targeting

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Abstract

A major goal in cancer gene therapy is to develop efficient gene transfer protocols that allow tissue-specific and tightly regulated expression of therapeutic genes. The ideal vector should efficiently transduce cancer cells with minimal toxicity on normal tissues and persistently express foreign genes. One of the most promising regulatory systems is the mifepristone/RU486-regulated system, which has much lower basal transcriptional activity and high inducibility. In this work, we modified this system by incorporating a cancer-specific promoter, the human telomerase reverse transcriptase (hTERT) promoter. By utilizing hTERT promoter to control the regulator, RU486 could specifically induce the expression of foreign genes in cancer cells but not in normal cells. In the context of this system, a dominant negative mutant of survivin (surDN) was controllably expressed in colorectal tumor cells. The surDN expression induced by RU486 showed a dosage- and time-dependent pattern. Regulated expression of surDN caused caspase-dependent apoptosis in colorectal tumor cells but had little effect on normal cells. Analysis of cell viability showed that RU486-induced expression of surDN suppressed colorectal tumor cell growth and had synergic effect in combination with chemotherapeutic agents. The potential of this system in cancer therapy was evaluated in experimental animals. Tumor xenograft models were established in nude mice with colorectal tumor cells, and RU486 was intraperitoneally administered. The results showed that conditional expression of surDN efficiently inhibited tumor growth in vivo and prolonged the life of tumor-burdened mice. Synergized with the chemotherapeutic drug cisplatin, regulated surDN expression completely suppressed tumor growth. These results indicated that this modified RU486-regulated system could be useful in cancer-targeting therapy.

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Abbreviations

hTERT:

human telomerase reverse transcriptase

SurDN:

survivin dominant negative mutant

GAL4 UAS17-mer :

17-mer GAL4 upstream activation sequence

References

  1. Wang Y, O’Malley BW Jr, Tsai SY, O’Malley BW (1994) A regulatory system for use in gene transfer. Proc Natl Acad Sci USA 91:8180–8184

    Article  PubMed  CAS  Google Scholar 

  2. Burcin MM, O’Malley BW, Tsai SY (1998) A regulatory system for target gene expression. Front Biosci 3:c1–c7

    PubMed  CAS  Google Scholar 

  3. Yaolin Wang, O’Malley BW, SY Tsai (1997) Inducible system designed for future gene therapy. Method Mol Med 63:401–413

    Google Scholar 

  4. Wang Y, Xu J, Pierson T, O’Malley BW, Tsai SY (1997) Positive and negative regulation of gene expression in eukaryotic cells with an inducible transcriptional regulator. Gene Ther 4:432–441

    Article  PubMed  CAS  Google Scholar 

  5. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  6. Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316

    Article  PubMed  CAS  Google Scholar 

  7. Reed JC (1999) Dysregulation of apoptosis in cancer. J Clin Oncol 17:2941–2953

    PubMed  CAS  Google Scholar 

  8. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

    Article  PubMed  CAS  Google Scholar 

  9. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656

    Article  PubMed  CAS  Google Scholar 

  10. Salvesen GS, Duckett CS (2002) IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 3:401–410

    Article  PubMed  CAS  Google Scholar 

  11. Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917–921

    Article  PubMed  CAS  Google Scholar 

  12. Altieri DC, Marchisio PC, Marchisio C (1999) Survivin apoptosis: an interloper between cell death and cell proliferation in cancer. Lab Invest 79:1327–1333

    PubMed  CAS  Google Scholar 

  13. Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54

    Article  PubMed  CAS  Google Scholar 

  14. Jiang X, Wilford C, Duensing S, Munger K, Jones G, Jones D (2001) Participation of Survivin in mitotic and apoptotic activities of normal and tumor-derived cells. J Cell Biochem 83:342–354

    Article  PubMed  CAS  Google Scholar 

  15. Ambrosini G, Adida C, Sirugo G, Altieri DC (1998) Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J Biol Chem 273:11177–11182

    Article  PubMed  CAS  Google Scholar 

  16. Olie RA et al (2000) A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer cells to chemotherapy. Cancer Res 60:2805–2809

    PubMed  CAS  Google Scholar 

  17. Lu B et al (2004) Survivin as a therapeutic target for radiation sensitization in lung cancer. Cancer Res 64:2840–2845

    Article  PubMed  CAS  Google Scholar 

  18. Uchida H et al (2004) Adenovirus-mediated transfer of siRNA against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Mol Ther 10:162–171

    Article  PubMed  CAS  Google Scholar 

  19. Wang L et al (2004) Prolonged and inducible transgene expression in the liver using gutless adenovirus: a potential therapy for liver cancer. Gastroenterology 126:278–289

    Article  PubMed  CAS  Google Scholar 

  20. Lin T et al (2002) Long-term tumor-free survival from treatment with the GFP-TRAIL fusion gene expressed from the hTERT promoter in breast cancer cells. Oncogene 21:8020–8028

    Article  PubMed  CAS  Google Scholar 

  21. Grossman D, Kim PJ, Schechner JS, Altieri DC (2001) Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc Natl Acad Sci USA 98:635–640

    Article  PubMed  CAS  Google Scholar 

  22. Cong YS, Wen J, Bacchetti S (1999) The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet 8:137–142

    Article  PubMed  CAS  Google Scholar 

  23. Adida C, Crotty PL, McGrath J, Berrebi D, Diebold J, Altieri DC (1998) Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am J Pathol 152:43–49

    PubMed  CAS  Google Scholar 

  24. Takakura M et al (1999) Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res 59:551–557

    PubMed  CAS  Google Scholar 

  25. Bilsland AE et al (2003) Selective ablation of human cancer cells by telomerase-specific adenoviral suicide gene therapy vectors expressing bacterial nitroreductase. Oncogene 22:370–380

    Article  PubMed  CAS  Google Scholar 

  26. Lu CD, Altieri DC, Tanigawa N (1998) Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res 58:1808–1812

    PubMed  CAS  Google Scholar 

  27. Liu T, Brouha B, Grossman D (2004) Rapid induction of mitochondrial events and caspase-independent apoptosis in Survivin-targeted melanoma cells. Oncogene 23:39–48

    Article  PubMed  CAS  Google Scholar 

  28. Furth PA et al (1994) Temporal control of gene expression in transgenic mice by a tetracycline- responsive promoter. Proc Natl Acad Sci USA 91:9302–9306

    Article  PubMed  CAS  Google Scholar 

  29. Rivera VM et al (1996) A humanized system for pharmacologic control of gene expression. Nat Med 2:1028–1032

    Article  PubMed  CAS  Google Scholar 

  30. No D, Yao T-P, Evans RM (1996) Ecdysone-inducible gene expression in mammalian cells and transgenic mice. Proc Natl Acad Sci USA 93:3346–3351

    Article  PubMed  CAS  Google Scholar 

  31. Abruzzese RV, McLaughlin FC, Smith LC, Nordstrom JL (2002) Regulated expression of plasmid-based gene therapies. Methods Mol Med 69:109–122

    PubMed  CAS  Google Scholar 

  32. Zou W et al (2004) A novel oncolytic adenovirus targeting to telomerase activity in tumor cells with potent. Oncogene 23:457–464

    Article  PubMed  CAS  Google Scholar 

  33. Lanson NA Jr, Friedlander PL, Schwarzenberger P, Kolls JK, Wang G (2003) Replication of an adenoviral vector controlled by the human telomerase reverse transcriptase promoter causes tumor-selective tumor lysis. Cancer Res 63:7936–7941

    PubMed  CAS  Google Scholar 

  34. Zaffaroni N et al (2002) Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. Cell Mol Life Sci 59:1406–1412

    Article  PubMed  CAS  Google Scholar 

  35. Tamm I et al (1998) IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 58:5315–5320

    PubMed  CAS  Google Scholar 

  36. Morsy MA et al (1998) An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Proc Natl Acad Sci USA 95:7866–7871

    Article  PubMed  CAS  Google Scholar 

  37. Morral N et al (1999) Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proc Natl Acad Sci USA 96:12816–12821

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Key Project of the Chinese Academy of Sciences (No. KSCX2-3-06), the National Natural Science Foundation of China (No. 30120160823), the Chinese National “863” High-Tech Project Foundation grant (No. 2002AA216021), and the Chinese National “973” Fundamental Research Project (No. 2004CB518804).

We thank Dr. BL Fang for providing us with the hTERT promoter. We also thank Lanying Sun for helping in cell culture, and Dr. Wang Jinhui at the University of Pennsylvania Medical Center and Children’s Hospital of Philadelphia for the critical reading of this manuscript.

Binghua Li and Junkai Fan contributed equally to this work.

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Correspondence to Xinyuan Liu.

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Li, B., Fan, J., Liu, X. et al. Suppression of colorectal tumor growth by regulated survivin targeting. J Mol Med 84, 1077–1086 (2006). https://doi.org/10.1007/s00109-006-0106-9

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