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Adenovirus-mediated N5 gene transfer inhibits tumor growth and metastasis of human carcinoma in nude mice

Cancer Gene Therapy volume 9, pages 665–672 (2002)Cite this article

Abstract

The therapeutic effectiveness of cancer therapy often relies on induction of apoptotic cell death. Gene-therapy–mediated induction of apoptosis, therefore, may provide an effective means to kill cancer cells. The N5 gene encodes a death-domain–containing protein (p84N5) that can trigger atypical apoptosis from within the nucleus, suggesting it may be a candidate for use as a gene therapy for cancer. In the present study, we test the potential utility of a recombinant adenovirus designed to express the N5 gene(AdN5) for the treatment of a variety of human cancers using in vitro and animal models. In vitro, adenoviral-mediated N5gene transfer inhibits the growth of five different tumor cell lines, but not a normal diploid fibroblast cell line. Adenoviral-mediated N5gene transfer also reduces the growth and metastasis of primary human tumors in subcutaneous and orthotopic xenograft mouse models. Reduction in tumor cell growth in vitro and in vivo correlates with increased expression of p84N5 and induction of apoptosis. The relative sensitivity of different human cancer cells to AdN5 or Adp53 varies, suggesting that AdN5 may be effective in tumors relatively resistant to p53 gene therapy. We conclude that N5 has potential utility for the gene therapy of cancer.

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References

  1. Jacobson MD, Weil M, Raff MC . Programmed cell death in animal development Cell 1997 88: 347–354

    Article  CAS  PubMed  Google Scholar 

  2. Vaux DL, Haecker G, Strasser A . An evolutionary perspective on apoptosis Cell 1994 76: 777–779

    CAS  PubMed  Google Scholar 

  3. Favrot M, Coll JL, Louis N, Negoescu A . Cell death and cancer: replacement of apoptotic genes and inactivation of death suppressor genes in therapy Gene Ther 1998 5: 728–739

    Article  CAS  PubMed  Google Scholar 

  4. Clary BM, Lyerly HK . Gene therapy and pancreatic cancer Surg Oncol Clin N Am 1998 7: 217–249

    Article  CAS  PubMed  Google Scholar 

  5. Aspinall RJ, Lemoine NR . Gene therapy for pancreatic and biliary malignancies Ann Oncol 1999 10: Suppl 4 188–192

    Article  PubMed  Google Scholar 

  6. Bouvet M, Bold RJ, Lee J et al. Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer Ann Surg Oncol 1998 5: 681–688

    Article  CAS  PubMed  Google Scholar 

  7. Kimura M, Tagawa M, Takenaga K et al. Inability to induce the alteration of tumorigenicity and chemosensitivity of p53-null human pancreatic carcinoma cells after the transduction of wild-type p53 gene Anticancer Res 1997 17: 879–883

    CAS  PubMed  Google Scholar 

  8. Durfee T, Mancini MA, Jones D, Elledge SJ, Lee W-H . The amino-terminal region of the retinoblastoma gene product binds a novel nuclear matrix protein that co-localizes to centers for RNA processing J Cell Biol 1994 127: 609–622

    Article  CAS  PubMed  Google Scholar 

  9. Feinstein E, Kimchi A, Wallach D, Boldin M, Varfolomeev E . The death domain: a module shared by proteins with diverse cellular functions Trends Biochem Sci 1995 20: 342–344

    Article  CAS  PubMed  Google Scholar 

  10. Doostzadeh-Cizeron J, Yin S, Goodrich DW . Apoptosis induced by the nuclear death domain protein p84N5 is associated with caspase-6 and NF-kB activation J Biol Chem 2000 275: 25336–25341

    Article  CAS  PubMed  Google Scholar 

  11. Doostzadeh-Cizeron J, Terry NHA, Goodrich DW . The nuclear death domain protein p84n5 activates a G2/M cell cycle checkpoint prior to the onset of apoptosis J Biol Chem 2001 276: 1127–1132

    Article  CAS  PubMed  Google Scholar 

  12. Doostzadeh-Cizeron J, Evans R, Yin S, Goodrich DW . Apoptosis induced by the nuclear death domain protein p84N5 is inhibited by association with Rb protein Mol Biol Cell 1999 10: 3251–3261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Goodwin EC, DiMaio D . Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways Proc Natl Acad Sci USA 2000 97: 12513–12518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wells SI, Francis DA, Karpova AY, Dowhanick JJ, Benson JD, Howley PM . Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21(CIP)-dependent pathways EMBO J 2000 19: 5762–5771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu L, Goodwin EC, Naeger LK et al. E2F-Rb complexes assemble and inhibit cdc25A transcription in cervical carcinoma cells following repression of human papillomavirus oncogene expression Mol Cell Biol 2000 20: 7059–7067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Masciullo V, Khalili K, Giordano A . The Rb family of cell cycle regulatory factors: clinical implications Int J Oncol 2000 17: 897–902

    CAS  PubMed  Google Scholar 

  17. Bartkova J, Lukas J, Bartek J . Aberrations of the G1- and G1/S-regulating genes in human cancer Prog Cell Cycle Res 1997 3: 211–220

    Article  CAS  PubMed  Google Scholar 

  18. Weinberg RA . The molecular basis of carcinogenesis: understanding the cell cycle clock Cytokines Mol Ther 1996 2: 105–110

    CAS  PubMed  Google Scholar 

  19. Sherr CJ . Cancer cell cycles Science 1996 274: 1672–1677

    Article  CAS  PubMed  Google Scholar 

  20. Vezeridis MP, Meitner PA, Tibbetts LM, Doremus CM, Tzanakakis G, Calabresi P . Heterogeneity of potential for hematogenous metastasis in a human pancreatic carcinoma J Surg Res 1990 48: 51–55

    Article  CAS  PubMed  Google Scholar 

  21. Yin S, Hung MC, Goodrich DW . Adenovirus-mediated N5 gene transfer inhibits tumor cell proliferation by induction of apoptosis Cancer Gene Ther 2000 7: 985–990

    Article  CAS  PubMed  Google Scholar 

  22. Huyghe BG, Liu X, Sutjipto S et al. Purification of a type 5 recombinant adenovirus encoding human p53 by column chromatography Hum Gene Ther 1995 6: 1403–1416

    Article  CAS  PubMed  Google Scholar 

  23. Zhang W-W, Fang X, Branch CD, Mazur W, French BA, Roth JA . Generation and identification of recombinant adenovirus by liposome-mediated transfection and PCR analysis Biotechniques 1993 15: 868–872

    CAS  PubMed  Google Scholar 

  24. Shi Q, Xiong Q, Wang B, Le X, Khan NA, Xie K . Influence of nitric oxide synthase II gene disruption on tumor growth and metastasis Cancer Res 2000 60: 2579–2583

    CAS  PubMed  Google Scholar 

  25. Shi Q, Xie K . Experimental animal models of pancreatic cancer Int J Oncol 2000 17: 217–225

    CAS  PubMed  Google Scholar 

  26. Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K . Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic Clin Cancer Res 1999 5: 3711–3721

    CAS  PubMed  Google Scholar 

  27. Clayman GL . The current status of gene therapy Semin Oncol 2000 27: 39–43

    CAS  PubMed  Google Scholar 

  28. Kigawa J, Terakawa N . Adenovirus-mediated transfer of a p53 gene in ovarian cancer Adv Exp Med Biol 2000 465: 207–214

    Article  CAS  PubMed  Google Scholar 

  29. Chen QR, Mixson AJ . Systemic gene therapy with p53 inhibits breast cancer: recent advances and therapeutic implications Frontiers Biosci 1998 3: D997–D1004

    Article  CAS  Google Scholar 

  30. Roth JA, Swisher SG, Meyn RE . p53 tumor suppressor gene therapy for cancer Oncology (Huntington) 1999 13: 148–154

    CAS  Google Scholar 

  31. Swisher SG, Roth JA, Nemunaitis J et al. Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer J Nat Can Inst 1999 91: 763–771

    Article  CAS  Google Scholar 

  32. Harris MP, Sutjipto S, Wills KN et al. Adenovirus-mediated p53 gene transfer inhibits growth of human tumor cells expressing mutant p53 protein Cancer Gene Ther 1996 3: 121–130

    CAS  PubMed  Google Scholar 

  33. Meng RD, Shih H, Prabhu NS, George DL, El-Deiry WS . Bypass of abnormal MDM2 inhibition of p53-dependent growth suppression Clin Cancer Res 1998 4: 251–259

    CAS  PubMed  Google Scholar 

  34. Vinyals A, Peinado MA, Gonzalez-Garrigues M, Monzo M, Bonfil RD, Fabra A . Failure of wild-type p53 gene therapy in human cancer cells expressing a mutant p53 protein Gene Ther 1999 6: 22–33

    Article  CAS  PubMed  Google Scholar 

  35. Liu T-J, Zhang W-W, Taylor DL, Roth JA, Goepfert H, Clayman GL . Growth suppression of human head and neck cancer cells by the introduction of a wild-type p53 gene via a recombinant adenovirus Cancer Res 1994 54: 3662–3667

    CAS  PubMed  Google Scholar 

  36. Hedlund TE, Meech SJ, Srikanth S et al. Adenovirus-mediated expression of Fas ligand induces apoptosis of human prostate cancer cells Cell Death Differ 1999 6: 175–182

    Article  CAS  PubMed  Google Scholar 

  37. Barton CM, McKie AB, Hogg A et al. Abnormalities of the RB1 and DCC tumor suppressor genes: uncommon in human pancreatic adenocarcinoma Mol Carcinog 1995 13: 61–69

    Article  CAS  PubMed  Google Scholar 

  38. Schutte M, Hruban RH, Geradts J et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas Cancer Res 1997 57: 3126–3130

    CAS  PubMed  Google Scholar 

  39. Todd MC, Sclafani RA, Langan TA . Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein Oncogene 2000 19: 258–264

    Article  CAS  PubMed  Google Scholar 

  40. Shew JY, Lin BT, Chen PL, Tseng BY, Yang-Feng TL, Lee WH . C-terminal truncation of the retinoblastoma gene product leads to functional inactivation Proc Natl Acad Sci USA 1990 87: 6–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rogatsky I, Trowbridge JM, Garabedian MJ . Glucocorticoid receptor-mediated cell cycle arrest is achieved through cell-specific transcriptional regulatory mechanisms Mol Cell Biol 1997 17: 3181–3193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kulp KS, Green SL, Vulliet PR . Iron deprivation inhibits cyclin-dependent kinase activity and decreases cyclin D/CDK4 protein levels in asynchronous MDA-MB-453 human breast cancer cells Exp Cell Res 1996 229: 60–68

    Article  CAS  PubMed  Google Scholar 

  43. Lebwohl DE, Muise-Helmericks R, Sepp-Lorenzino L et al. A truncated cyclin D1 gene encodes a stable mRNA in a human breast cancer cell line Oncogene 9: 1925–1929

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Acknowledgements

We thank Dr Ta-Jen Liu for providing AdGFP and Adp53. Dr Wen-Hwa Lee kindly provided the 5E10 anti-N5 antibody. We thank other members of the Goodrich laboratory for helpful discussions. We acknowledge Carolyn Cooke for expert technical assistance. This work was supported by the National Institutes of Health Grant CA-70292 (D.W.G.) and RPG-00-054-01-CMS from the American Cancer Society (K.X.).

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, 14263, New York, USA

    Shenmin Yin & David W Goodrich

  2. Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Wang Bailiang & Keping Xie

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  1. Shenmin Yin
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  4. David W Goodrich
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Correspondence to David W Goodrich.

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Yin, S., Bailiang, W., Xie, K. et al. Adenovirus-mediated N5 gene transfer inhibits tumor growth and metastasis of human carcinoma in nude mice. Cancer Gene Ther 9, 665–672 (2002). https://doi.org/10.1038/sj.cgt.7700484

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