Asian Pacific Journal of Cancer Prevention

  • 제13권8호
  • /
  • Pages.4147-4151
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  • 2012
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  • 1513-7368(pISSN)
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  • 2476-762X(eISSN)
아시아태평양암예방학회 (Asian Pacific Journal of Cancer Prevention)
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Silencing of PDK1 Gene Expression by RNA Interference Suppresses Growth of Esophageal Cancer

  • Yu, Jing (Department of Pathology, the First Affiliated Hospital of Zhengzhou University and Henan Key Laboratory for Tumor Pathology) ;
  • Chen, Kui-Sheng (Department of Pathology, the First Affiliated Hospital of Zhengzhou University and Henan Key Laboratory for Tumor Pathology) ;
  • Li, Ya-Nan (Department of Pathology, the First Affiliated Hospital of Zhengzhou University and Henan Key Laboratory for Tumor Pathology) ;
  • Yang, Juan (Department of Pathology, the First Affiliated Hospital of Zhengzhou University and Henan Key Laboratory for Tumor Pathology) ;
  • Zhao, Lu (Department of Pathology, the First Affiliated Hospital of Zhengzhou University and Henan Key Laboratory for Tumor Pathology)
  • 발행 : 2012.08.31
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초록

The current study was conducted to explore the inhibitory effects of a small interfering RNA (siRNA) on 3-phosphoinositide-dependent protein kinase 1 (PDK1) expression in esophageal cancer 9706 (EC9706) cells and the influence on their biological behavior. After transfection of a synthesized PDK1 siRNA, PDK1 mRNA and protein expression and the phosphorylation level of the downstream Akt protein were assessed using RT-PCR and Western blot analysis. Proliferation, apoptosis, cell invasion and in vivo tumor formation capacity were also investigated using MTT, flow cytometry, Transwell invasion trials, and nude mouse tumor transplantion, respectively. PDK1 siRNA effectively suppressed PDK1 mRNA and protein expression, and down-regulated the phosphorylation level of the Akt protein in the EC9706 cells (P < 0.05). It also inhibited cell proliferation and invasion, and promoted apoptosis; such effects were particularly obvious at 48 h and 72 h after transfection (P < 0.05). Growth of transplanted tumors was inhibited in nude mice, with decreased PDK1 expression in tumor tissues. PDK1 may be closely correlated with proliferation, apoptosis and invasion of esophageal cancer cells and thus may serve as an effective target for gene therapy.

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참고문헌

  1. Bilanges B, Stokoe D (2005). Direct comparison of the specificity of gene silencing using antisense oligonucleotides and RNAi. Biochemcal J, 388, 573-83. https://doi.org/10.1042/BJ20041956
  2. Carnero A (2010). The PKB/AKT pathway in cancer. Curr Pharm Des, 16, 34-4. https://doi.org/10.2174/138161210789941865
  3. Caron RW, Yacoub A, Li M, et a1 (2005). Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival. Mol Cancer Ther, 4, 257-70.
  4. Fire A, Xu S, Montgomery MK, et a1 (1998). Potent and specific interference by double-stranded RNA in Caenorhabditis elegans. Nature, 391, 806-11. https://doi.org/10.1038/35888
  5. Granville CA, Memmott RM, Gills JJ, Dennis PA (2006). Handicapping the race to develop inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway. Clin Cancer Res, 12, 679-89. https://doi.org/10.1158/1078-0432.CCR-05-1654
  6. Hildebrandt MA, Yang H, Hung MC, et a1 (2009). Genetic variations in the PI3K/PTEN /AKT/mTOR pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy. J Clin Oncol, 27, 857-71. https://doi.org/10.1200/JCO.2008.17.6297
  7. Hsieh AC, Bo R, Manola J, et a1 (2004). A library of siRNA duplexes targeting the phosphoinositide 3-kinase pathway: determinants of gene silencing for use in cell-based screens. Nucleic Acids Research, 32, 893-901. https://doi.org/10.1093/nar/gkh238
  8. Iorns E, Lord CJ, Ashworth A (2009). Parallel RNAi and compound screens identify the PDK1 pathway as a target for tamoxifen sensitisation. Biochem J, 417, 361-70. https://doi.org/10.1042/BJ20081682
  9. Jiang H, Shang X, Wu H, et al (2009). Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol, 8, 25-33.
  10. Knowles MA, Platt FM, Ross RL, Hurst CD (2009). Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer. Cancer Metastasis Rev, 28, 305-16. https://doi.org/10.1007/s10555-009-9198-3
  11. Li B, Cheung PY, Wang X, Tsao SW, et al (2007). Id-1 activation of PI3K/Akt/NFkB signaling pathway and its significance in promoting survival of esophageal cancer cells. Carcinogenesis, 28, 2313-20. https://doi.org/10.1093/carcin/bgm152
  12. Liang K, Lu Y, Li X, et al (2006). Differential roles of phosphoinositide-dependent protein kinase-1 and akt1 expression and phosphorylation in breast cancer cell resistance to Paclitaxel, Doxorubicin, and gemcitabine. Mol Pharmacol, 70, 1045-52. https://doi.org/10.1124/mol.106.023333
  13. Liu Y, Wang J, Wu M, et al (2009). Down-regulation of 3-phosphoinositide-dependent protein kinase-1 levels inhibits migration and experimental metastasis of human breast cancer cells. Mol Cancer Res, 7, 944-55. https://doi.org/10.1158/1541-7786.MCR-08-0368
  14. Martelli AM, Evangelisti C, Chiarini F, McCubrey JA (2010). The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget, 1, 89-103.
  15. Matheny RW Jr, Adamo ML (2009). Current perspectives on Akt Akt-ivation and Akt-ions. Exp Biol Med, 234, 1264-70. https://doi.org/10.3181/0904-MR-138
  16. Oh YK, Park TG (2009). siRNA delivery systems for cancer treatment. Advanced Drug Delivery Reviews, 61, 850-62. https://doi.org/10.1016/j.addr.2009.04.018
  17. Peifer C, Alessi DR (2009). New anti-cancer role for PDK1 inhibitors: preventing resistance to tamoxifen. Biochem J, 417, e5-7. https://doi.org/10.1042/BJ20082243
  18. Tamguney T, Zhang C, Fiedler D, Shokat K, Stokoe D (2008). Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells. Exp Cell Res, 314, 2299-312. https://doi.org/10.1016/j.yexcr.2008.04.006
  19. Watanabe S, Sato K, Okazaki Y, et al (2009). Activation of PI3KAKT pathway in oral epithelial dysplasia and early cancer of tongue. Bull Tokyo Dent Coll, 50, 125-33. https://doi.org/10.2209/tdcpublication.50.125
  20. Wilkins C, Dishongh R, Moore SC, et al (2005). RNA interference is an antiviral defence mechanism in Caenorhabditis elegans. Nature, 436, 1044-7. https://doi.org/10.1038/nature03957
  21. Wu M, Wu J, Xu Y, et al (2009). Small interfering RNA PDK1 inhibits breast cancer cell line invasion and metastasis, Chinese J Clin Oncol, 36, 697-700.

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