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Tumor-specific gene expression using the survivin promoter is further increased by hypoxia

Abstract

Increasing evidence indicates that survivin, an inhibitor of apoptosis protein (IAP), is expressed in human cancer cells but is absent from most normal adult tissues. Here, we examined the feasibility of using a survivin promoter (Sur-P) to direct therapeutic expression of a proapoptotic gene specifically in human tumor cells. First, we demonstrated that this promoter was highly active in human tumor cells but not in normal cells. Second, we found that Sur-P activity was upregulated by hypoxia in tumor cells. Third, to further enhance this promoter's activity under hypoxia, we added a hypoxia-responsive element (HRE) from the vascular endothelial growth factor gene promoter in its 5′ region, and showed that this combination resulted in a further increase in the level of gene expression in hypoxic tumor cells. Finally, we demonstrated that expression of an autocatalytic reverse caspase-3 gene by this promoter specifically induced apoptotic cell death in human tumor cells but not in normal cells. These findings support the use of promoters Sur-P or chimeric HRE-Sur-P for generating novel vectors for cancer gene therapy.

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References

  1. Nettelbeck DM, Jerome V, Muller R . Gene therapy: designer promoters for tumour targeting. Trends Genet 2000; 16: 174–181.

    Article  CAS  PubMed  Google Scholar 

  2. Robson T, Hirst DG . Transcriptional targeting in cancer gene therapy. J Biomed Biotechnol 2003; 2003: 110–137.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Brand K et al. Tumor cell-specific transgene expression prevents liver toxicity of the adeno-HSVtk/GCV approach. Gene Therapy 1998; 5: 1363–1371.

    Article  CAS  PubMed  Google Scholar 

  4. Hernandez-Alcoceba R, Pihalja M, Qian D, Clarke MF . New oncolytic adenoviruses with hypoxia- and estrogen receptor-regulated replication. Hum Gene Ther 2002; 13: 1737–1750.

    Article  CAS  PubMed  Google Scholar 

  5. Lee SJ et al. Novel prostate-specific promoter derived from PSA and PSMA enhancers. Mol Ther 2002; 6: 415–421.

    Article  CAS  PubMed  Google Scholar 

  6. Bui LA et al. In vivo therapy of hepatocellular carcinoma with a tumor-specific adenoviral vector expressing interleukin-2. Hum Gene Ther 1997; 8: 2173–2182.

    Article  CAS  PubMed  Google Scholar 

  7. Kitazono M, Chuman Y, Aikou T, Fojo T . Adenovirus HSV-TK construct with thyroid-specific promoter: enhancement of activity and specificity with histone deacetylase inhibitors and agents modulating the camp pathway. Int J Cancer 2002; 99: 453–459.

    Article  CAS  PubMed  Google Scholar 

  8. Altieri DC . Survivin and apoptosis control. Adv Cancer Res 2003; 88: 31–52.

    Article  CAS  PubMed  Google Scholar 

  9. Reed JC . The Survivin saga goes in vivo. J Clin Invest 2001; 108: 965–969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Holcik M, Gibson H, Korneluk RG . XIAP: apoptotic brake and promising therapeutic target. Apoptosis 2001; 6: 253–261.

    Article  CAS  PubMed  Google Scholar 

  11. Li F et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998; 396: 580–584.

    Article  CAS  PubMed  Google Scholar 

  12. Altieri DC . Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003; 3: 46–54.

    Article  CAS  PubMed  Google Scholar 

  13. Li F . Survivin study: what is the next wave? J Cell Physiol 2003; 197: 8–29.

    Article  CAS  PubMed  Google Scholar 

  14. Tanaka K et al. Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res 2000; 6: 127–134.

    CAS  PubMed  Google Scholar 

  15. Satoh K et al. Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer 2001; 92: 271–278.

    Article  CAS  PubMed  Google Scholar 

  16. Asanuma K et al. A role for survivin in radioresistance of pancreatic cancer cells. Jpn J Cancer Res 2002; 93: 1057–1062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Kennedy SM et al. Prognostic importance of survivin in breast cancer. Br J Cancer 2003; 88: 1077–1083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Miller M, Smith D, Windsor A, Kessling A . Survivin gene expression and prognosis in recurrent colorectal cancer. Gut 2001; 48: 137–138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang L, Cao Z, Yan H, Wood WC . Co-existence of high levels of apoptotic signaling and inhibitor of apoptosis proteins in human tumor cells: implication for cancer specific therapy. Cancer Res 2003; 63: 6815–6824.

    CAS  PubMed  Google Scholar 

  21. Mesri M et al. Cancer gene therapy using a survivin mutant adenovirus. J Clin Invest 2001; 108: 981–990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Hockel M, Vaupel P . Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93: 266–276.

    Article  CAS  PubMed  Google Scholar 

  24. Semenza GL . Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 2000; 35: 71–103.

    Article  CAS  PubMed  Google Scholar 

  25. Shibata T, Giaccia AJ, Brown JM . Hypoxia-inducible regulation of a prodrug-activating enzyme for tumor-specific gene therapy. Neoplasia 2002; 4: 40–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ruan H et al. A hypoxia-regulated adeno-associated virus vector for cancer-specific gene therapy. Neoplasia 2001; 3: 255–263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Post DE, Van Meir EG . A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy. Oncogene 2003; 22: 2065–2072.

    Article  CAS  PubMed  Google Scholar 

  28. Post DE, Van Meir EG . Generation of bidirectional hypoxia/HIF-responsive expression vectors to target gene expression to hypoxic cells. Gene Therapy 2001; 8: 1801–1807.

    Article  CAS  PubMed  Google Scholar 

  29. Srinivasula SM et al. Generation of constitutively active recombinant caspases-3 and -6 by rearrangement of their subunits. J Biol Chem 1998; 273: 10107–10111.

    Article  CAS  PubMed  Google Scholar 

  30. Bao R et al. Activation of cancer-specific gene expression by the survivin promoter. J Natl Cancer Inst 2002; 94: 522–528.

    Article  CAS  PubMed  Google Scholar 

  31. Li F, Altieri DC . Transcriptional analysis of human survivin gene expression. Biochem J 1999; 344 Pt 2: 305–311.

    CAS  PubMed  Google Scholar 

  32. Roth JA, Cristiano RJ . Gene therapy for cancer: what have we done and where are we going? J Natl Cancer Inst 1997; 89: 21–39.

    Article  CAS  PubMed  Google Scholar 

  33. Bos R et al. Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 2003; 97: 1573–1581.

    Article  PubMed  Google Scholar 

  34. Zhong H et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 1999; 59: 5830–5835.

    CAS  PubMed  Google Scholar 

  35. Semenza GL . HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med 2002; 8: S62–S67.

    Article  CAS  PubMed  Google Scholar 

  36. Ghafar MA et al. Acute hypoxia increases the aggressive characteristics and survival properties of prostate cancer cells. Prostate 2003; 54: 58–67.

    Article  PubMed  Google Scholar 

  37. Dachs GU, Tozer GM . Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation. Eur J Cancer 2000; 36: 1649–1660.

    Article  CAS  PubMed  Google Scholar 

  38. Semenza GL et al. Hypoxia-inducible factor 1: from molecular biology to cardiopulmonary physiology. Chest 1998; 114: 40S–45S.

    Article  CAS  PubMed  Google Scholar 

  39. Shibata T, Giaccia AJ, Brown JM . Development of a hypoxia-responsive vector for tumor-specific gene therapy. Gene Therapy 2000; 7: 493–498.

    Article  CAS  PubMed  Google Scholar 

  40. Greco O et al. Novel chimeric gene promoters responsive to hypoxia and ionizing radiation. Gene Therapy 2002; 9: 1403–1411.

    Article  CAS  PubMed  Google Scholar 

  41. Su H, Arakawa-Hoyt J, Kan YW . Adeno-associated viral vector-mediated hypoxia response element-regulated gene expression in mouse ischemic heart model. Proc Natl Acad Sci USA 2002; 99: 9480–9485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. He TC et al. A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 1998; 95: 2509–2514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We express our sincere thanks to Dr Bert Vogelstein at Johns Hopkins University for pAdtrackCMV and p-shuttle vectors, and Dr Emad S Alnemri at Thomas Jefferson University for providing us with the reverse caspase-3 gene. This research project is supported in part by the Breast Cancer Research Program of Avon Foundation (to LY), NIH Grants # CA95643 (to LY), CA80017 (to LY), CA87830 NS41403. CA86335 (to EGVM) and The Brain Tumor Society (to EGVM and DEP).

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Yang, L., Cao, Z., Li, F. et al. Tumor-specific gene expression using the survivin promoter is further increased by hypoxia. Gene Ther 11, 1215–1223 (2004). https://doi.org/10.1038/sj.gt.3302280

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