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hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity

Gene Therapy volume 9, pages 30–37 (2002)Cite this article

Abstract

We recently showed that the human telomerase reverse transcriptase (hTERT) promoter induces tumor-specific Bax gene expression and selectively kills various human cancer cells both in vitro and in xenograft tumors. However, it remains unclear whether the hTERT promoter can be used to induce transgene expression in syngenic tumors in mice and whether Bax gene expression driven by the hTERT promoter will cause long-term, stem cell-related toxicity. To address these questions, we tested hTERT promoter-driven, adenovirus-mediated Bax transgene expression in an established syngenic mouse tumor model and its effects on tumor and normal murine tissues. The hTERT promoter was highly active in several murine tumor cell lines and a transformed cell line, but not in non-transformed and normal murine cell lines. The hTERT promoter induced tumor-specific Bax gene expression in mouse UV-2237m fibrosarcoma cells both in vitro and in vivo and suppressed syngenic tumor growth in immune-competent mice with no obvious acute or long-term toxic effects. Moreover, hTERT promoter-driven transgene expression in human CD34+ bone marrow progenitor cells had effects similar to those observed in other normal human cells, suggesting that the hTERT promoter is much less active in CD34+ cells than in tumor cells. Together, our data demonstrate that the hTERT promoter may allow the use of proapoptotic genes for cancer treatment without noticeable effects on progenitor cells.

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References

  1. Thompson C.B. . Apoptosis in the pathogenesis and treatment of disease Science 1995 267: 1456 1456

    Article  CAS  PubMed  Google Scholar 

  2. Roth J.A. et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer Nat Med 1996 1996: 2 2

    Google Scholar 

  3. Shinoura N. et al. Apoptosis by retrovirus- and adenovirus-mediated gene transfer of Fas ligand to glioma cells: implications for gene therapy Hum Gene Ther 1998 9: 1983 1983

    Article  CAS  PubMed  Google Scholar 

  4. Pataer A. et al. Adenoviral Bak overexpression mediates caspase-dependent tumor killing Cancer Res 2000 60: 788 788

    CAS  PubMed  Google Scholar 

  5. Kagawa S. et al. Antitumor effect of adenovirus-mediated Bax gene transfer on p53-sensitive and p53-resistant cancer lines Cancer Res 2000 60: 1157 1157

    CAS  PubMed  Google Scholar 

  6. Shinoura N. et al. Adenovirus-mediated transfer of caspase-8 augments cell death in gliomas: implication for gene therapy Hum Gene Ther 2000 11: 1123 1123

    Article  CAS  PubMed  Google Scholar 

  7. Vile R.G., Hart I.R. . In vitro and in vivo targeting of gene expression to melanoma cells Cancer Res 1993 53: 962 962

    CAS  PubMed  Google Scholar 

  8. Osaki T. et al. Gene therapy for carcinoembryonic antigen-producing human lung cancer cells by cell type-specific expression of herpes simplex virus thymidine kinase gene Cancer Res 1994 54: 5258 5258

    CAS  PubMed  Google Scholar 

  9. Chen L. et al. Breast cancer selective gene expression and therapy mediated by recombinant adenoviruses containing the DF3/MUC1 promoter J Clin Invest 1995 96: 2775 2775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Parr M.J. et al. Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector Nat Med 1997 3: 1145 1145

    Article  CAS  PubMed  Google Scholar 

  11. Gu J. et al. Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers Cancer Res 2000 60: 5359 5359

    CAS  PubMed  Google Scholar 

  12. Koga S. et al. A novel telomerase-specific gene therapy: gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter Hum Gene Ther 2000 11: 1397 1397

    Article  CAS  PubMed  Google Scholar 

  13. Kim N.W. et al. Specific association of human telomerase activity with immortal cells and cancer Science 1994 266: 2011 2011

    Article  CAS  PubMed  Google Scholar 

  14. Shay J.W., Bacchetti S. . A survey of telomerase activity in human cancer Eur J Cancer 33 1997: 787 787

    Google Scholar 

  15. Oreffo V.I. et al. Decreased expression of the adenomatous polyposis coli (Apc) and mutated in colorectal cancer (Mcc) genes in mouse lung neoplasia Mol Carcinog 1998 21: 37 37

    Article  CAS  PubMed  Google Scholar 

  16. Kagawa S. et al. A binary adenoviral vector system for expressing high levels of the proapoptotic gene bax Gene Therapy 2000 7: 75 75

    Article  CAS  PubMed  Google Scholar 

  17. Lu W., Fidle I.J., Dong Z. . Eradication of primary murine fibrosarcomas and induction of systemic immunity by adenovirus-mediated interferon β gene therapy Cancer Res 1999 59: 5202 5202

    CAS  PubMed  Google Scholar 

  18. Watanabe T. et al. Gene transfer into human bone marrow hematopoietic cells mediated by adenovirus vectors Blood 1996 87: 5032 5032

    CAS  PubMed  Google Scholar 

  19. Feldman E. et al. Adenovirus-mediated alpha interferon (IFN-α) gene transfer into CD34+ cells and CML mononuclear cells Stem Cells 1997 15: 386 386

    Article  CAS  PubMed  Google Scholar 

  20. Howard D.S. et al. Genetic manipulation of primitive leukemic and normal hematopoietic cells using a novel method of adenovirus-mediated gene transfer Leukemia 1999 13: 1608 1608

    Article  CAS  PubMed  Google Scholar 

  21. Greenberg R.A. et al. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation Oncogene 1999 18: 1219 1219

    Article  CAS  PubMed  Google Scholar 

  22. Yin L., Hubbard A.K., Giardina C. . NF-κB regulates transcription of the mouse telomerase catalytic subunit J Biol Chem 2000 275: 36671 36671

    Article  CAS  PubMed  Google Scholar 

  23. Wang J. et al. Myc activates telomerase Gene Dev 1998 12: 1769 1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takakura M. et al. 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 1999 59: 551 551

    CAS  PubMed  Google Scholar 

  25. Horikawa I., Cable P.L., Afshari C., Barrett J.C. . Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene Cancer Res 1999 59: 826 826

    CAS  PubMed  Google Scholar 

  26. Kyo S. et al. Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT) Nucleic Acid Res 2000 28: 669 669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tzukerman M. et al. Identification of a novel transcription factor binding element involved in the regulation by differentiation of the human telomerase (hTERT) promoter Mol Biol Cell 11 2000: 4381 4381

    Google Scholar 

  28. Morrison S.J., Prowse K.R., Ho P., Weissman I.L. . Telomerase activity in hematopoietic cells is associated with self-renewal potential Immunity 1996 5: 207 207

    Article  CAS  PubMed  Google Scholar 

  29. Yui J., Chiu C.-P., Lansdorp P.M. . Telomerase activity in candidate stem cells from fetal liver and adult bone marrow Blood 1998 91: 3255 3255

    CAS  PubMed  Google Scholar 

  30. Zhang W. et al. Telomerase activity in human acute myelogenous leukemia: inhibition of telomerase activity by differentiation-inducing agents Clin Cancer Res 1996 2: 799 799

    CAS  PubMed  Google Scholar 

  31. Andreeff M. et al. Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid Leukemia 1999 13: 1881 1881

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Teresa McQueen for isolating human bone marrow CD34+ cells, Dr Isaiah J Fidler for providing us with the UV-2237m murine tumor cells. This study was funded by a research project grant from the American Cancer Society (RPG-00-274-01-MGO to BF); an Institutional Start Up Fund grant (to BF); a development award from the WM Keck Center for Cancer Gene Therapy of The University of Texas MD Anderson Cancer Center (BF); an NIH program project grant (CA78778-01A1), and an NIH Core Grant for Medium and Vectors (CA 16672). JG is an MD Anderson Odyssey Program Fellow supported by the Kimberly-Clark Endowment for New and Innovative Research.

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Gu, JA Roth & B Fang

  2. Department of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Andreeff

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  1. J Gu
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  2. M Andreeff
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Gu, J., Andreeff, M., Roth, J. et al. hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity. Gene Ther 9, 30–37 (2002). https://doi.org/10.1038/sj.gt.3301619

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