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Effects of DNAzymes targeting Aurora kinase A on the growth of human prostate cancer

Cancer Gene Therapy volume 15, pages 517–525 (2008)Cite this article

Abstract

Aurora kinase A has been demonstrated to be involved in the malignant progression of many types of cancer including prostate cancer, we therefore hypothesized that Aurora kinase A might work as a valuable target for prostate cancer treatment. To test this hypothesis, we used DNAzyme technology to inhibit Aurora kinase A expression and evaluated the effects of DNAzymes as therapeutic agents to treat prostate cancer. In an in vitro cleavage assay, we found that a DNAzyme (DZ2) targeting Aurora kinase A could effectively cleave Aurora kinase A mRNA. When transfected into the prostate cancer cell line PC3, DZ2 was found to strongly inhibit the expression of Aurora kinase A examined by western blot analysis, and thus suppressed cell growth, arrested the progression of cell cycle, induced cell apoptosis and attenuated cell migration, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay, flow cytometry and Boyden chamber assay. Through in vivo study, we also found that DZ2 could significantly inhibit the growth of human prostate cancer xenografts in nude mice. In conclusion, DZ2 could effectively attenuate malignant progression of prostate cancer both in vitro and in vivo, suggesting that DNAzyme targeting Aurora kinase A may be used as a valuable therapy to treat prostate cancer.

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References

  1. Meraldi P, Honda R, Nigg EA . Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr Opin Genet Dev 2004; 14: 29–36.

    Article  CAS  PubMed  Google Scholar 

  2. Giet R, Prigent C . Aurora/Iplp-related kinases, a new oncogenic family of mitotic serine-threonine kinases. J Cell Sci 1999; 112: 3591–3601.

    CAS  PubMed  Google Scholar 

  3. Sun M, Wang G, Paciga JE, Feldman RI, Yuan ZQ, Ma XL et al. AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol 2001; 159: 431–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bar-Shira A, Pinthus JH, Rozovsky U, Goldstein M, Sellers WR, Yaron Y et al. Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft. Cancer Res 2002; 62: 6803–6807.

    CAS  PubMed  Google Scholar 

  5. Lee EC, Frolov A, Li R, Ayala G, Greenberg NM . Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 2006; 66: 4996–5002.

    Article  CAS  PubMed  Google Scholar 

  6. Zhao FY, Qu Y, Zhang L, Mu DZ, Huang X, Wei DP . Effect of Aurora A on biological phenotypes of prostate cancer cells. Sichuan Da Xue Xue Bao Yi Xue Ban 2007; 38: 302–305.

    CAS  PubMed  Google Scholar 

  7. Isaka Y . DNAzymes as potential therapeutic molecules. Curr Opin Mol Ther 2007; 9: 132–136.

    CAS  PubMed  Google Scholar 

  8. Schubert S, Gul DC, Grunert HP, Zeichhardt H, Erdmann VA, Kurreck J . RNA cleaving ‘10–23’ DNAzymes with enhanced stability and activity. Nucleic Acids Res 2003; 31: 5982–5992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sclhubert S, Kurreck J . Ribozyme and deoxyribozyme strategies for medical applications. Curr Drug Targets 2004; 5: 667–681.

    Article  Google Scholar 

  10. Khachigian LM . DNAzymes: cutting a path to a new class of therapeutics. Curr Opin Mol Ther 2002; 4: 119–121.

    CAS  PubMed  Google Scholar 

  11. Qu Y, Wang Z, Huang X, Wan C, Yang CL, Liu B et al. Circadian telomerase activity and DNA synthesis for timing peptide administration. Peptides 2003; 24: 363–369.

    Article  CAS  PubMed  Google Scholar 

  12. Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M et al. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell 2003; 114: 585–598.

    Article  CAS  PubMed  Google Scholar 

  13. Crane R, Gadea B, Littlepage L, Wu H, Ruderman JV . Aurora A, meiosis and mitosis. Biol Cell 2004; 96: 215–229.

    Article  CAS  PubMed  Google Scholar 

  14. Warner SL, Bearss DJ, Han H, Von Hoff DD . Targeting Aurora-2 kinase in cancer. Mol Cancer Ther 2003; 2: 589–595.

    Article  CAS  PubMed  Google Scholar 

  15. Keen N, Taylor S . Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004; 4: 927–936.

    Article  CAS  PubMed  Google Scholar 

  16. Dutertre S, Descamps S, Prigent C . On the role of Aurora A in centrosome function. Oncogene 2002; 21: 6175–6183.

    Article  CAS  PubMed  Google Scholar 

  17. Scrittori L, Hans F, Angelov D, Charra M, Prigent C, Dimitrov S . pEg2 Aurora-A kinase, histone H3 phosphorylation, and chromosome assembly in xenopus egg extract. J Biol Chem 2001; 276: 30002–30010.

    Article  CAS  PubMed  Google Scholar 

  18. Huang YS, Jung MY, Sarkissian M, Richter JD . N-Methyl-Daspartate recepter signaling results in Aurora kinase-catalyzed CPEB phosphorylation and CaMKII mRNA polyadenylation at synapses. EMBO J 2002; 21: 2139–2148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Giet R, McLean D, Descamps S, Lee MJ, Raff JW, Prigent C et al. Drosophila Aurora A kinase is required to localize D-TACC to centrosomes and to regulate astral microtubules. J Cell Biol 2002; 156: 437–451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gastro A, Mandart E, Lorca T, Galas S . Involvement of Aurora A kinase during meiosis I–II transition in Xenopus oocytes. J Biol Chem 2003; 278: 2236–2241.

    Article  Google Scholar 

  21. Kufer TA, Sillje HH, Korner R, Gruss OJ, Meraldi P, Nigg EA . Human TPX2 is required for targeting Aurora-A kinase to the spindle. J Cell Biol 2002; 158: 617–623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cazales M, Schmitt E, Montembault E, Dozier C, Prigent C, Ducommun B . CDC25B phosphorylation by Aurora-A occurs at the G2/M transition and is inhibited by DNA damage. Cell Cycle 2005; 4: 1233–1238.

    Article  CAS  PubMed  Google Scholar 

  23. Yang H, Ou CC, Feldman RI, Nicosia SV, Kruk PA, Cheng JQ . Aurora A kinase regulates telomerase activity through c-Myc in human ovarian and breast epithelial cells. Cancer Res 2004; 64: 463–467.

    Article  CAS  PubMed  Google Scholar 

  24. Saretzki G . Telomerase inhibition as cancer therapy. Cancer Lett 2003; 194: 209–219.

    Article  CAS  PubMed  Google Scholar 

  25. Wu JC, Chen TY, Yu CT, Tsai SJ, Hsu JM, Tang MJ et al. Identification of V23RalA-Ser194 as a critical mediator for Aurora-A-induced cellular motility and transformation by small pool expression screening. J Biol Chem 2005; 280: 9013–9022.

    Article  CAS  PubMed  Google Scholar 

  26. Guan Z, Wang XR, Zhu XF, Huang XF, Xu J, Wang LH et al. Aurora-A, a negative prognostic marker, increases migration and decreases radiosensitivity in cancer cells. Cancer Res 2007; 67: 10436–10444.

    Article  CAS  PubMed  Google Scholar 

  27. Kimura M, Matsuda Y, Yoshioka T, Sumi N, Okano Y . Identification and characterization of STK12/Aik2: a human gene related to Aurora of Drosophila and yeast IPL1. Cytogenet Cell Genet 1998; 82: 147–152.

    Article  CAS  PubMed  Google Scholar 

  28. Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004; 10: 262–267.

    Article  CAS  PubMed  Google Scholar 

  29. Manfredi MG, Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W et al. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci USA 2007; 104: 4106–4111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hata T, Furukawa T, Sunamura M, Egawa S, Motoi F, Ohmura N et al. RNA interference targeting aurora kinase a suppresses tumor growth and enhances the taxane chemosensitivity in human pancreatic cancer cells. Cancer Res 2005; 65: 2899–2905.

    Article  CAS  PubMed  Google Scholar 

  31. Dass CR . Preclinical anticancer activity of DNA-based cleavage molecules. Drug Dev Ind Pharm 2006; 32: 1–5.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 30570623 and 30770748 to Dezhi Mu), Doctoral Program of Ministry of Education of China (No. 20050610094 to Yi Qu and No. 20070610092 to Dezhi Mu), China Medical Board of New York (00-722 to Dezhi Mu). We thank Stephanie Cambier from University of California San Francisco for proofing the paper.

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Authors and Affiliations

  1. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China

    Y Qu, M Mao, F Zhao, Y Xiong & D Mu

  2. Department of Immunology and Cell Biology, West China Medical Center, Sichuan University, Chengdu, China

    L Zhang & C Yang

  3. Department of Urology, The People's Hospital of Sichuan Province, Chengdu, China

    X Huang

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Correspondence to D Mu.

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Qu, Y., Zhang, L., Mao, M. et al. Effects of DNAzymes targeting Aurora kinase A on the growth of human prostate cancer. Cancer Gene Ther 15, 517–525 (2008). https://doi.org/10.1038/cgt.2008.22

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