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AKT1 Inhibitory DNAzymes Inhibit Cell Proliferation and Migration of Thyroid Cancer Cells

  • Yang, Le (Department of Endocrinology, The People's Hospital of Jilin Province) ;
  • He, Jin-Ting (Department of Neurology, China-Japan Friendship Hospital, Jilin University) ;
  • Guan, Hong (Department of Endocrinology, The People's Hospital of Jilin Province) ;
  • Sun, Ya-Dong (Department of Endocrinology, The People's Hospital of Jilin Province)
  • Published : 2013.04.30

Abstract

AKT1 is a member of the serine/threoine AGC protein kinase family involved in thyroid cancer metabolism, growth, proliferation and survival. It is overexpressed in thyroid tumors. In this study, we designed two AKT1 specific DNAzymes (DRz1 and DRz2) that target AKT1 mRNA. The results showed that DRz1 could decrease the expression of AKT1 by 58%. Furthermore, DRz1 significantly inhibited cell proliferation, induced apoptosis and inhibited invasion in SW597 cells. In addition, down-regulation of survivin expression was associated with decreased caspase-3, VEGF and MMP2 in SW597 cells after 24 h. In our study, the efficacy of DRz1 in decreasing AKT1 protein levels were better than DRz2. AKT1-DRz1 might have anti-tumorigenic activity and may provide the basis for a novel therapeutic intervention in thyroid cancer treatment.

References

  1. Hollenstein M, Hipolito C, Lam C, Perrin D (2008). In vitro selection of a DNAzyme with three modified nucleotides. Nucleic Acids Symp Ser (Oxf), 2008, 73-4.
  2. Cheng S, Niv MY (2010). Molecular dynamics simulations and elastic network analysis of protein kinase B (Akt/PKB) inactivation. J Chem Inf Model, 50, 1602-10. https://doi.org/10.1021/ci100076j
  3. Gijsen M, King P, Perera T, et al (2010). HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer. PLoS Biol, 8, e1000563. https://doi.org/10.1371/journal.pbio.1000563
  4. Hou P, Liu D, Shan Y, Hu S, et al (2007). Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin Cancer Res, 13, 1161-70. https://doi.org/10.1158/1078-0432.CCR-06-1125
  5. Li Y, Sen D (1997). Toward an efficient DNAzyme. Biochemistry, 36, 5589-99. https://doi.org/10.1021/bi962694n
  6. Kucukalic-Selimovic E, Alagic J, Valjevac A, et al (2012). The Akt inhibitor MK2206 synergizes, but perifosine antagonizes, the BRAF(V600E) inhibitor PLX4032 and the MEK1/2 inhibitor AZD6244 in the inhibition of thyroid cancer cells. J Clin Endocrinol Metab, 97, E173-82. https://doi.org/10.1210/jc.2011-1054
  7. Kucukalic-Selimovic E, Alagic J, Valjevac A, et al (2012). The value of serum thyreoglobulin levels and whole body (I-131) scintigraphy in the follow-up of the thyroid cancer patients after thyroidectomy. Coll Antropol, 36, 67-71.
  8. Mansley MK, Wilson SM (2010). Effects of nominally selective inhibitors of the kinases PI3K, SGK1 and PKB on the insulin-dependent control of epithelial $Na^+$ absorption. Br J Pharmacol, 161, 571-88. https://doi.org/10.1111/j.1476-5381.2010.00898.x
  9. Mo N, Li ZQ, Li J, Cao YD (2012). Curcumin Inhibits TGFbeta1-Induced MMP-9 and Invasion through ERK and Smad Signaling in Breast Cancer MDA-MB-231 Cells. Asian Pac J Cancer Prev, 13, 5709-14. https://doi.org/10.7314/APJCP.2012.13.11.5709
  10. Pitt S C, Chen H (2008). The phosphatidylinositol 3-kinase/akt signaling pathway in medullary thyroid cancer. Surgery, 144, 721-4. https://doi.org/10.1016/j.surg.2008.06.028
  11. Ponce D, Maturana JL, Cabello P, et al (2010). Phosphorylation of AKT/PKB by CK2 is necessary for the AKT-dependent up-regulation of beta-catenin transcriptional activity. J Cell Physiol, 226, 1953-9.
  12. Tang M, Iijima M, Kamimura Y, et al (2011). Disruption of PKB signaling restores polarity to cells lacking tumor suppressor PTEN. Mol Biol Cell, 22, 437-47. https://doi.org/10.1091/mbc.E10-06-0522
  13. Taskin S, Dunder I, Erol E, et al (2012). Roles of E-cadherin and cyclooxygenase enzymes in predicting different survival patterns of optimally cytoreduced serous ovarian cancer patients. Asian Pac J Cancer Prev, 13, 5715-9. https://doi.org/10.7314/APJCP.2012.13.11.5715
  14. Tian Y, Mao C (2005). DNAzyme amplification of molecular beacon signal. Talanta, 67, 532-7. https://doi.org/10.1016/j.talanta.2005.06.044
  15. Verma N, Tripathi SK, Chaudhury I, et al (2010). iNOStargeted 10-23 DNAzyme reduces LPS-induced systemic inflammation and mortality in mice. Shock, 33, 493-9.
  16. Wang TH, Li WT, Yu SH, et al (2008). The use of 10-23 DNAzyme to selectively destroy the allele of mRNA with a unique purine-pyrimidine dinucleotide. Oligonucleotides, 18, 295-9. https://doi.org/10.1089/oli.2008.0138
  17. Zhao ZG, Guo XG, Ba CX, et al (2012). Overweight, Obesity and Thyroid Cancer Risk, a Meta-analysis of Cohort Studies. J Int Med Res, 40, 2041-50. https://doi.org/10.1177/030006051204000601

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