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Antitumor effects of bladder cancer-specific adenovirus carrying E1A-androgen receptor in bladder cancer

Gene Therapy volume 19, pages 1065–1074 (2012)Cite this article

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Abstract

The high frequency of recurrence and poor survival rate of bladder cancer demand exploration of novel strategies. Gene therapy via adenovirus has shown promising potential for the treatment of tumors. We constructed a bladder cancer-specific adenovirus carrying E1A-androgen receptor (AR) under the control of UPII promoter and prostate stem cell antigen enhancer (PSCAE), designated as Ad/PSCAE/UPII/E1A-AR, and investigated its antitumor effects in vitro and in vivo. We demonstrated that Ad/PSCAE/UPII/E1A-AR could be selectively replicated in bladder tumor cell lines (5637, BIU87, EJ and T24) when compared with control adenovirus Ad/PSCAE/UPII/Luc. However, there was no evidence of cytotoxicity for normal human bladder cell line SV-HUC-1 and hepatoma cell line SMMC7721. AR agonist R1881 could strengthen the oncolytic effect of Ad/PSCAE/UPII/E1A-AR in bladder cancer cells. In addition, we demonstrated that intratumoral injection of Ad/PSCAE/UPII/E1A-AR into established subcutaneous human EJ tumors in nude mice could significantly regress the growth of tumor and markedly prolong survival for tumor-bearing mice; on the other hand, saline-treated tumors continued to grow rapidly. Our studies indicate that Ad/PSCAE/UPII/E1A-AR could effectively treat bladder cancer in vitro and in vivo. Furthermore, our findings provide a promising therapeutic modality for the treatment of bladder cancer.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71–96.

    Article  PubMed  Google Scholar 

  2. Voutsinas GE, Stravopodis DJ . Molecular targeting and gene delivery in bladder cancer therapy. J BUON 2009; 14 (Suppl 1): S69–S78.

    PubMed  Google Scholar 

  3. Kompier LC, Lurkin I, van der Aa MN, van Rhijn BW, van der Kwast TH, Zwarthoff EC . FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS One 2010; 5: e13821.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Frisch SM . Tumor suppression activity of adenovirus E1a protein: anoikis and the epithelial phenotype. Adv Cancer Res 2001; 80: 39–49.

    Article  CAS  PubMed  Google Scholar 

  5. Hubberstey AV, Pavliv M, Parks RJ . Cancer therapy utilizing an adenoviral vector expressing only E1A. Cancer Gene Ther 2002; 9: 321–329.

    Article  CAS  PubMed  Google Scholar 

  6. Yang Y, McKerlie C, Borenstein SH, Lu Z, Schito M, Chamberlain JW et al. Transgenic expression in mouse lung reveals distinct biological roles for the adenovirus type 5 E1A 243- and 289-amino-acid proteins. J Virol 2002; 76: 8910–8919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83: 835–839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lu ML, Schneider MC, Zheng Y, Zhang X, Richie JP . Caveolin-1 interacts with androgen receptor. A positive modulator of androgen receptor mediated transactivation. J Biol Chem 2001; 276: 13442–13451.

    Article  CAS  PubMed  Google Scholar 

  9. Marcelli M, Stenoien DL, Szafran AT, Simeoni S, Agoulnik IU, Weigel NL et al. Quantifying effects of ligands on androgen receptor nuclear translocation, intranuclear dynamics, and solubility. J Cell Biochem 2006; 98: 770–788.

    Article  CAS  PubMed  Google Scholar 

  10. Tomura A, Goto K, Morinaga H, Nomura M, Okabe T, Yanase T et al. The subnuclear three-dimensional image analysis of androgen receptor fused to green fluorescence protein. J Biol Chem 2001; 276: 28395–28401.

    Article  CAS  PubMed  Google Scholar 

  11. Szafran AT, Szwarc M, Marcelli M, Mancini MA . Androgen receptor functional analyses by high throughput imaging: determination of ligand, cell cycle, and mutation-specific effects. PLoS One 2008; 3: e3605.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Marcelli M, Ittmann M, Mariani S, Sutherland R, Nigam R, Murthy L et al. Androgen receptor mutations in prostate cancer. Cancer Res 2000; 60: 944–949.

    CAS  PubMed  Google Scholar 

  13. Wilson CM, McPhaul MJ . A and B forms of the androgen receptor are expressed in a variety of human tissues. Mol Cell Endocrinol 1996; 120: 51–57.

    Article  CAS  PubMed  Google Scholar 

  14. Boorjian SA, Heemers HV, Frank I, Farmer SA, Schmidt LJ, Sebo TJ et al. Expression and significance of androgen receptor coactivators in urothelial carcinoma of the bladder. Endocr Relat Cancer 2009; 16: 123–137.

    Article  CAS  PubMed  Google Scholar 

  15. Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 2010; 17: 535–546.

    Article  CAS  PubMed  Google Scholar 

  16. Azuma K, Nakashiro K, Sasaki T, Goda H, Onodera J, Tanji N et al. Anti-tumor effect of small interfering RNA targeting the androgen receptor in human androgen-independent prostate cancer cells. Biochem Biophys Res Commun 2010; 391: 1075–1079.

    Article  CAS  PubMed  Google Scholar 

  17. Miyamoto H, Yang Z, Chen YT, Ishiguro H, Uemura H, Kubota Y et al. Promotion of bladder cancer development and progression by androgen receptor signals. J Natl Cancer Inst 2007; 99: 558–568.

    Article  CAS  PubMed  Google Scholar 

  18. Wu JT, Han BM, Yu SQ, Wang HP, Xia SJ . Androgen receptor is a potential therapeutic target for bladder cancer. Urology 2010; 75: 820–827.

    Article  PubMed  Google Scholar 

  19. Hoti N, Li Y, Chen CL, Chowdhury WH, Johns DC, Xia Q et al. Androgen receptor attenuation of Ad5 replication: implications for the development of conditionally replication competent adenoviruses. Mol Ther 2007; 15: 1495–1503.

    Article  PubMed  Google Scholar 

  20. He XD, Wang ZP, Wei HY, Zhou Q, Wang DG, Tian JQ et al. Construction of urothelium-specific recombinant adenovirus and its inhibition in bladder cancer cell. Urol Int 2009; 82: 209–213.

    Article  PubMed  Google Scholar 

  21. Halloran CM, Ghaneh P, Shore S, Greenhalf W, Zumstein L, Wilson D et al. 5-Fluorouracil or gemcitabine combined with adenoviral-mediated reintroduction of p16INK4A greatly enhanced cytotoxicity in Panc-1 pancreatic adenocarcinoma cells. J Gene Med 2004; 6: 514–525.

    Article  CAS  PubMed  Google Scholar 

  22. Leja J, Dzojic H, Gustafson E, Oberg K, Giandomenico V, Essand M . A novel chromogranin—a promoter-driven oncolytic adenovirus for midgut carcinoid therapy. Clin Cancer Res 2007; 13: 2455–2462.

    Article  CAS  PubMed  Google Scholar 

  23. Xie X, Hsu JL, Choi MG, Xia W, Yamaguchi H, Chen CT et al. A novel hTERT promoter-driven E1A therapeutic for ovarian cancer. Mol Cancer Ther 2009; 8: 2375–2382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Campos SK, Barry MA . Current advances and future challenges in adenoviral vector biology and targeting. Curr Gene Ther 2007; 7: 189–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR . Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res 1997; 57: 2559–2563.

    CAS  PubMed  Google Scholar 

  26. Takahashi M, Sato T, Sagawa T, Lu Y, Sato Y, Iyama S et al. E1B-55K-deleted adenovirus expressing E1A-13S by AFP-enhancer/promoter is capable of highly specific replication in AFP-producing hepatocellular carcinoma and eradication of established tumor. Mol Ther 2002; 5: 627–634.

    Article  CAS  PubMed  Google Scholar 

  27. Li Y, Chen Y, Dilley J, Arroyo T, Ko D, Working P et al. Carcinoembryonic antigen-producing cell-specific oncolytic adenovirus, OV798, for colorectal cancer therapy. Mol Cancer Ther 2003; 2: 1003–1009.

    CAS  PubMed  Google Scholar 

  28. Li X, Jung C, Liu YH, Bae KH, Zhang YP, Zhang HJ et al. Anti-tumor efficacy of a transcriptional replication-competent adenovirus, Ad-OC-E1a, for osteosarcoma pulmonary metastasis. J Gene Med 2006; 8: 679–689.

    Article  CAS  PubMed  Google Scholar 

  29. Li Y, Kacka M, Thompson M, Hsieh JT, Koeneman KS . Conditionally replicating adenovirus therapy utilizing bone sialoprotein promoter (Ad-BSP-E1a) in an in vivo study of treating androgen-independent intraosseous prostate cancer. Urol Oncol 2011; 29: 624–633.

    Article  CAS  PubMed  Google Scholar 

  30. Shirakawa T, Hamada K, Zhang Z, Okada H, Tagawa M, Kamidono S et al. A cox-2 promoter-based replication-selective adenoviral vector to target the cox-2-expressing human bladder cancer cells. Clin Cancer Res 2004; 10: 4342–4348.

    Article  CAS  PubMed  Google Scholar 

  31. Ramesh N, Ge Y, Ennist DL, Zhu M, Mina M, Ganesh S et al. CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor—armed oncolytic adenovirus for the treatment of bladder cancer. Clin Cancer Res 2006; 12: 305–313.

    Article  CAS  PubMed  Google Scholar 

  32. Li SM, Zhang ZT, Chan S, McLenan O, Dixon C, Taneja S et al. Detection of circulating uroplakin-positive cells in patients with transitional cell carcinoma of the bladder. J Urol 1999; 162: 931–935.

    Article  CAS  PubMed  Google Scholar 

  33. Wang D, Wang Z, Tian J, He X, Chowdhury WH, Zhang X et al. Prostate stem cell antigen enhancer and uroplakin II promoter based bladder cancer targeted tissue-specific vector. Urol Oncol 2010; 28: 164–169.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang J, Ramesh N, Chen Y, Li Y, Dilley J, Working P et al. Identification of human uroplakin II promoter and its use in the construction of CG8840, a urothelium-specific adenovirus variant that eliminates established bladder tumors in combination with docetaxel. Cancer Res 2002; 62: 3743–3750.

    CAS  PubMed  Google Scholar 

  35. Zhu H, Zhang ZA, Xu C, Huang G, Zeng X, Wei S et al. Targeting gene expression of the mouse uroplakin II promoter to human bladder cells. Urol Res 2003; 31: 17–21.

    PubMed  Google Scholar 

  36. Zhu HJ, Zhang ZQ, Zeng XF, Wei SS, Zhang ZW, Guo YL . Cloning and analysis of human uroplakin II promoter and its application for gene therapy in bladder cancer. Cancer Gene Ther 2004; 11: 263–272.

    Article  CAS  PubMed  Google Scholar 

  37. Liao X, Tang S, Thrasher JB, Griebling TL, Li B . Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer. Mol Cancer Ther 2005; 4: 505–515.

    Article  CAS  PubMed  Google Scholar 

  38. Boorjian S, Ugras S, Mongan NP, Gudas LJ, You X, Tickoo SK et al. Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer. Urology 2004; 64: 383–388.

    Article  PubMed  Google Scholar 

  39. Tollefson AE, Scaria A, Hermiston TW, Ryerse JS, Wold LJ, Wold WS . The adenovirus death protein (E3-11.6K) is required at very late stages of infection for efficient cell lysis and release of adenovirus from infected cells. J Virol 1996; 70: 2296–2306.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhu M, Bristol JA, Xie Y, Mina M, Ji H, Forry-Schaudies S et al. Linked tumor-selective virus replication and transgene expression from E3-containing oncolytic adenoviruses. J Virol 2005; 79: 5455–5465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sachs MD, Rauen KA, Ramamurthy M, Dodson JL, De Marzo AM, Putzi MJ et al. Integrin alpha(v) and coxsackie adenovirus receptor expression in clinical bladder cancer. Urology 2002; 60: 531–536.

    Article  PubMed  Google Scholar 

  42. Stoff-Khalili MA, Stoff A, Rivera AA, Mathis JM, Everts M, Wang M et al. Gene transfer to carcinoma of the breast with fiber-modified adenoviral vectors in a tissue slice model system. Cancer Biol Ther 2005; 4: 1203–1210.

    Article  CAS  PubMed  Google Scholar 

  43. Okegawa T, Nutahara K, Pong RC, Higashihara E, Hsieh JT . Enhanced transgene expression in urothelial cancer gene therapy with histone deacetylase inhibitor. J Urol 2005; 174: 747–752.

    Article  CAS  PubMed  Google Scholar 

  44. Sachs MD, Ramamurthy M, Poel H, Wickham TJ, Lamfers M, Gerritsen W et al. Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells. Cancer Gene Ther 2004; 11: 477–486.

    Article  CAS  PubMed  Google Scholar 

  45. Hoti N, Chowdhury W, Hsieh JT, Sachs MD, Lupold SE, Rodriguez R . Valproic acid, a histone deacetylase inhibitor, is an antagonist for oncolytic adenoviral gene therapy. Mol Ther 2006; 14: 768–778.

    Article  PubMed  Google Scholar 

  46. El-Zawahry A, Lu P, White SJ, Voelkel-Johnson C . In vitro efficacy of AdTRAIL gene therapy of bladder cancer is enhanced by trichostatin A-mediated restoration of CAR expression and downregulation of cFLIP and Bcl-XL. Cancer Gene Ther 2006; 13: 281–289.

    Article  CAS  PubMed  Google Scholar 

  47. Haviv YS, Blackwell JL, Kanerva A, Nagi P, Krasnykh V, Dmitriev I et al. Adenoviral gene therapy for renal cancer requires retargeting to alternative cellular receptors. Cancer Res 2002; 62: 4273–4281.

    CAS  PubMed  Google Scholar 

  48. Kanerva A, Wang M, Bauerschmitz GJ, Lam JT, Desmond RA, Bhoola SM et al. Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses. Mol Ther 2002; 5: 695–704.

    Article  CAS  PubMed  Google Scholar 

  49. van Beusechem VW, Mastenbroek DC, van den Doel PB, Lamfers ML, Grill J, Wurdinger T et al. Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. Gene Therapy 2003; 10: 1982–1991.

    Article  CAS  PubMed  Google Scholar 

  50. Burke J . Virus therapy for bladder cancer. Cytokine Growth Factor Rev 2010; 21: 99–102.

    Article  CAS  PubMed  Google Scholar 

  51. Zhang X, Godbey WT . Preclinical evaluation of a gene therapy treatment for transitional cell carcinoma. Cancer Gene Ther 2011; 18: 34–41.

    Article  CAS  PubMed  Google Scholar 

  52. Tao Z, Connor RJ, Ashoori F, Dinney CP, Munsell M, Philopena JA et al. Efficacy of a single intravesical treatment with Ad-IFN/Syn 3 is dependent on dose and urine IFN concentration obtained: implications for clinical investigation. Cancer Gene Ther 2006; 13: 125–130.

    Article  CAS  PubMed  Google Scholar 

  53. Kuball J, Wen SF, Leissner J, Atkins D, Meinhardt P, Quijano E et al. Successful adenovirus-mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation. J Clin Oncol 2002; 20: 957–965.

    Article  CAS  PubMed  Google Scholar 

  54. Pagliaro LC, Keyhani A, Williams D, Woods D, Liu B, Perrotte P et al. Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: a phase I study of p53 gene therapy. J Clin Oncol 2003; 21: 2247–2253.

    Article  CAS  PubMed  Google Scholar 

  55. Wood M, Perrotte P, Onishi E, Harper ME, Dinney C, Pagliaro L et al. Biodistribution of an adenoviral vector carrying the luciferase reporter gene following intravesical or intravenous administration to a mouse. Cancer Gene Ther 1999; 6: 367–372.

    Article  CAS  PubMed  Google Scholar 

  56. Paielli DL, Wing MS, Rogulski KR, Gilbert JD, Kolozsvary A, Kim JH et al. Evaluation of the biodistribution, persistence, toxicity, and potential of germ-line transmission of a replication-competent human adenovirus following intraprostatic administration in the mouse. Mol Ther 2000; 1: 263–274.

    Article  CAS  PubMed  Google Scholar 

  57. Ramesh N, Memarzadeh B, Ge Y, Frey D, VanRoey M, Rojas V et al. Identification of pretreatment agents to enhance adenovirus infection of bladder epithelium. Mol Ther 2004; 10: 697–705.

    Article  CAS  PubMed  Google Scholar 

  58. Mi J, Li ZY, Ni S, Steinwaerder D, Lieber A . Induced apoptosis supports spread of adenovirus vectors in tumors. Hum Gene Ther 2001; 12: 1343–1352.

    Article  CAS  PubMed  Google Scholar 

  59. Liu C, Zhang Y, Liu MM, Zhou H, Chowdhury W, Lupold SE et al. Evaluation of continuous low dose rate versus acute single high dose rate radiation combined with oncolytic viral therapy for prostate cancer. Int J Radiat Biol 2010; 86: 220–229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Onimaru M, Ohuchida K, Nagai E, Mizumoto K, Egami T, Cui L et al. Combination with low-dose gemcitabine and hTERT-promoter-dependent conditionally replicative adenovirus enhances cytotoxicity through their crosstalk mechanisms in pancreatic cancer. Cancer Lett 2010; 294: 178–186.

    Article  CAS  PubMed  Google Scholar 

  61. Wang W, Sima N, Kong D, Luo A, Gao Q, Liao S et al. Selective targeting of HPV-16 E6/E7 in cervical cancer cells with a potent oncolytic adenovirus and its enhanced effect with radiotherapy in vitro and vivo. Cancer Lett 2010; 291: 67–75.

    Article  CAS  PubMed  Google Scholar 

  62. Xie Y, Sheng W, Miao J, Xiang J, Yang J . Enhanced antitumor activity by combining an adenovirus harboring ING4 with cisplatin for hepatocarcinoma cells. Cancer Gene Ther 2011; 18: 176–188.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National High-tech R&D Program of China (863 Program) (Grant No. 2008AA02Z421) and National Natural Science Foundation of China (Grant No. 30772177/H1619). We thank John Hopkins University for the gift of R1881, Xiang-dong He and De-gui Wang for helpful suggestions and comments, Hui-fang Zhang for carrying out the electron microscopic analysis (Lanzhou University Basic Medical College) and Jun Yan for carrying out the statistical analysis (Lanzhou University Basic Medical College).

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Authors and Affiliations

  1. Urologic Clinical Center of Gansu Province, Key Laboratory of Gansu Province, Institute of Urology, The Second Hospital of Lanzhou University, Lanzhou, China

    Z Zhai, Z Wang, S Fu, J Lu, R Li, H Zhang, S Li & Z Hou

  2. School of Basic Medical Sciences, Lanzhou University, Lanzhou, China

    F Wang

  3. School of Clinical Medicine, Shandong University, Shandong, China

    H Wang

  4. James Buchanan Brady Urology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    R Rodriguez

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  1. Z Zhai
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Zhai, Z., Wang, Z., Fu, S. et al. Antitumor effects of bladder cancer-specific adenovirus carrying E1A-androgen receptor in bladder cancer. Gene Ther 19, 1065–1074 (2012). https://doi.org/10.1038/gt.2011.180

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