A Single Therapeutic miRNA Rescues the Oncolysis of Androgen Activated Prostate Specific Virus in Androgen Independent Cell Model

DOI: 10.4236/jct.2012.36131   PDF   HTML   XML   3,565 Downloads   5,640 Views  


Prostate specific conditionally replicating adenoviruses (CRAd) are made by placing a tissue specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). However, one major problem associated with these vectors is their dependency for androgen receptor (AR), to transactivate the immediate early gene of the virus. This absolute necessity of androgens for prostate specific promoters renders them less useful in patients that have undergone or are currently on total androgen ablation therapy. Therefore, an alternative approach is needed for the existing vectors to be useful in clinical settings. To overcome this problem, we have generated a prostate specific CRAd by introducing a single therapeutic miRNA (miR-34c) that was identified in our library screen to synergize with viral oncolysis. Overexpression of miR-34c from the backbone of virus not only helped in suppressing the proliferation of AR positive cells but also rescued the oncolysis of androgen activated prostate specific virus in androgen independent cell model. To our knowledge this is the first report describing the utility of a single therapeutic miRNA construct to rescue viral oncolysis in advanced androgen resistant AR negative prostate cancer cell line model.

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T. Johnson, Z. Khan, S. Mustafa, K. Desai and N. Höti, "A Single Therapeutic miRNA Rescues the Oncolysis of Androgen Activated Prostate Specific Virus in Androgen Independent Cell Model," Journal of Cancer Therapy, Vol. 3 No. 6, 2012, pp. 1012-1019. doi: 10.4236/jct.2012.36131.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] N. Craft, C. Chhor, C. Tran, A. Belldegrun, J. DeKernion, O. N. Witte, J. Said, R. E. Reiter and C. L. Sawyers, “Evidence for Clonal Outgrowth of Androgen-Independent Prostate Cancer Cells from Androgen-Dependent Tumors through a Two-Step Process,” Cancer Research, Vol. 59, No. 19, 1999, pp. 5030-5036.
[2] T. Hakkarainen, M. Rajecki, M. Sarparanta, M. Tenhunen, A. J. Airaksinen, R. A. Desmond, K. Kairemo and A. Hemminki, “Targeted Radiotherapy for Prostate Cancer with an Oncolytic Adenovirus Coding for Human Sodium Iodide Symporter,” Clinical Cancer Research, Vol. 15, No. 17, 2009, pp. 5396-5403. doi:10.1158/1078-0432.CCR-08-2571
[3] M. S. Ferguson, N. R. Lemoine and Y. Wang, “Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles,” Advances in Virology, Vol. 2012, 2012, Article ID: 805629.
[4] N. Hoti, W. H. Chowdhury, S. Mustafa, J. Ribas, M. Castanares, T. Johnson, M. Liu, S. E. Lupold and R. Rodriguez, “Armoring CRAds with p21/Waf-1 shRNAs: The Next Generation of Oncolytic Adenoviruses,” Cancer Gene Therapy, Vol. 17, No. 8, 2010, pp. 585-597. doi:10.1038/cgt.2010.15
[5] R. D. Gerard and D. Collen, “Adenovirus Gene Therapy for Hypercholesterolemia, Thrombosis and Restenosis,” Cardiovascular Research, Vol. 35, No. 3, 1997, pp. 451-458. doi:10.1016/S0008-6363(97)00134-X
[6] M. Cristofanilli, S. Krishnamurthy, L. Guerra, K. Broglio, B. Arun, D. J. Booser, K. Menander, J. Van Wart Hood, V. Valero and G. N. Hortobagyi, “A Nonreplicating Adenoviral Vector That Contains the Wild-Type p53 Transgene Combined with Chemotherapy for Primary Breast Cancer: Safety, Efficacy, and Biologic Activity of a Novel Gene-Therapy Approach,” Cancer, Vol. 107, No. 5, 2006, pp. 935-944. doi:10.1002/cncr.22080
[7] E. J. Small, M. A. Carducci, J. M. Burke, R. Rodriguez, L. Fong, L. van Ummersen, D. C. Yu, J. Aimi, D. Ando, P. Working, D. Kirn and G. Wilding, “A Phase I Trial of Intravenous CG7870, a Replication-Selective, Prostate-Specific Antigen-Targeted Oncolytic Adenovirus, for the Treatment of Hormone-Refractory, Metastatic Prostate Cancer,” Molecular Therapy, Vol. 14, No. 1, 2006, pp. 107-117. doi:10.1016/j.ymthe.2006.02.011
[8] T. L. DeWeese, H. van der Poel, S. Li, B. Mikhak, R. Drew, M. Goemann, U. Hamper, R. DeJong, N. Detorie, R. Rodriguez, T. Haulk, A. M. DeMarzo, S. Piantadosi, D. C. Yu, Y. Chen, D. R. Henderson, M. A. Carducci, W. G. Nelson and J. W. Simons, “A Phase I Trial of CV706, a Replication-Competent, PSA Selective Oncolytic Adenovirus, for the Treatment of Locally Recurrent Prostate Cancer Following Radiation Therapy,” Cancer Research, Vol. 61, No. 20, 2001, pp. 7464-7472.
[9] N. Hoti, Y. Li, C. L. Chen, W. H. Chowdhury, D. C. Johns, Q. Xia, A. Kabul, J. T. Hsieh, M. Berg, G. Ketner, S. E. Lupold and R. Rodriguez, “Androgen Receptor Attenuation of Ad5 Replication: Implications for the Development of Conditionally Replication Competent Adenoviruses,” Molecular Therapy, Vol. 15, No. 8, 2007, pp. 1495-1503. doi:10.1038/sj.mt.6300223
[10] J. Lindzey, M. V. Kumar, M. Grossman, C. Young and D. J. Tindall, “Molecular Mechanisms of Androgen Action,” Vitamins & Hormones, Vol. 49, 1994, pp. 383-432. doi:10.1016/j.bbr.2011.03.031.
[11] E. P. Gelmann, “Molecular Biology of the Androgen Receptor,” Journal of Clinical Oncology, Vol. 20, No. 13, 2002, pp. 3001-3015. doi:10.1200/JCO.2002.10.018
[12] Z. Culig, H. Klocker, G. Bartsch and A. Hobisch, “Androgen Receptors in Prostate Cancer,” Endocrine-Related Cancer, Vol. 9, No. 3, 2002, pp. 155-170. doi:10.1677/erc.0.0090155
[13] Z. Hagman, O. Larne, A. Edsjo, A. Bjartell, R. A. Ehrnstrom, D. Ulmert, H. Lilja and Y. Ceder, “miR-34c Is Downregulated in Prostate Cancer and Exerts Tumor Suppressive Functions,” International Journal of Cancer, Vol. 127, No. 12, pp. 2768-2776. doi:10.1002/ijc.25269
[14] Y. K. Kim and V. N. Kim, “Processing of Intronic microRNAs,” EMBO Journal, Vol. 26, No. 3, 2007, pp. 775-783. doi:10.1038/sj.emboj.7601512
[15] M. Maugeri-Sacca, V. Coppola, D. Bonci and R. De Maria, “MicroRNAs and Prostate Cancer: From Preclinical Research to Translational Oncology,” Cancer Journal, Vol. 18, No. 3, pp. 253-261. doi:10.1097/PPO.0b013e318258b5b6
[16] H. Hermeking, “The miR-34 Family in Cancer and Apoptosis,” Cell Death & Differentiation, Vol. 17, No. 2, pp. 193-199. doi:10.1038/cdd.2009.56
[17] S. E. Lupold, T. A. Kudrolli, W. H. Chowdhury, P. Wu and R. Rodriguez, “A Novel Method for Generating and Screening Peptides and Libraries Displayed on Adenovirus Fiber,” Nucleic Acids Research, Vol. 35, No. 20, 2007, p. e138. doi:10.1093/nar/gkm914
[18] M. Satoh, H. Wang, S. Ishidoya, H. Abe, T. Moriya, H. Hamada and Y. Arai, “Oncolytic Virotherapy for Prostate Cancer by E1A, E1B Mutant Adenovirus,” Urology, Vol. 70, No. 6, 2007, pp. 1243-1248. doi:10.1016/j.urology.2007.09.031
[19] D. C. Yu, Y. Chen, M. Seng and J. Dilley, “The Addition of Adenovirus Type 5 Region E3 Enables Calydon Virus 787 to Eliminate Distant Prostate Tumor Xenografts,” Cancer Research, Vol. 59, No. 17, 1999, pp. 4200-4203.

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