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The Effects of Antisense AKT2 RNA on the Inhibition of Malignant Glioma Cell Growth in vitro and in vivo

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Summary

The oncogenic role of AKT2 in the development of malignant gliomas was examined by using antisense approach. AKT2 expression was significantly inhibited in rat C6 glioma cells transfected with antisense AKT2 cDNA construct (LXSN–AS–AKT2). In addition, the transfected cells proliferated at a lowered level and apoptosis was induced. For in vivo studies, parental C6 cells and C6 cells transfected with LXSN–AS–AKT2 were implanted stereotactically into the right caudate nucleus of SD rats (control C6 group and transfected group). The rats bearing well-established C6 gliomas were treated with LXSN–AS–AKT2 DNA or LXSN (empty vector)-lipofectamine complexes intratumorally (treated group and control treated group). The mean survival of the rats of control C6 group and treated control group was 17.8±0.92 days and 17.5±1.10 days, respectively. The mean survival of the rats of transfected and treated group was significantly prolonged. MR images revealed distinct cerebral tumor foci in all of the control rats, whereas four rats in transfected group did not develop tumors and the tumor foci in five rats of treated group were regressed and disappeared. The expression of AKT2, PCNA, MMP2/9, and cyclin D were inhibited in the tumors of rats in transfected and treated groups while GFAP expression was increased. These results suggest that AKT pathway may play an important role in the development and progression of gliomas. Anti-AKT approach will open a new perspective for a targeted molecular therapy of malignant gliomas.

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References

  1. RM Agosti M Leuthold WJ Gullick MG Yarsagil OD Wiester (1992) ArticleTitleExpression of the epidermal growth factor receptor in astrocytic tumors is specially associated with glioblastoma multiforme Virchows Arch (A) Pathol Anat 420 321–325 Occurrence Handle1:STN:280:DyaK383jtVWruw%3D%3D

    CAS  Google Scholar 

  2. AJ Ekstrand CD James WK Cavence B Selliger RF Patterson VP Collins (1991) ArticleTitleGenes for epidermal growth factor receptor, transforming growth factor α and epidermal growth factor and their expression in human gliomas in vivo Cancer Res 51 2164–2172 Occurrence Handle2009534 Occurrence Handle1:CAS:528:DyaK3MXisVWkurw%3D

    PubMed  CAS  Google Scholar 

  3. Liu X, Pu P: Expression of epidermal growth factor receptor gene in human gliomas. J Neurochem 67(Suppl): S 11A (Abstract), 1996

  4. JA Takahashi H Mori M Fukumoto K Igarashi M Jaye Y Oda H Kikuchi M Hatanaka (1990) ArticleTitleGene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissue Proc Natl Scad Sci USA 87 5710–5714 Occurrence Handle1:CAS:528:DyaK3cXlsV2ktL8%3D

    CAS  Google Scholar 

  5. A Guha K Dashner PM Black JA Wagner CD Stiles (1995) ArticleTitleExpression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop Int J Cancer 60 168–173 Occurrence Handle7829210 Occurrence Handle1:STN:280:DyaK2M7jtVahtA%3D%3D Occurrence Handle10.1002/ijc.2910600206

    Article  PubMed  CAS  Google Scholar 

  6. M Hermanson K Funa M Haartman L Claesson-Welsh CH Heldin B Westermark M Nister (1992) ArticleTitlePlatelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops Cancer Res 52 3213–3219 Occurrence Handle1317261 Occurrence Handle1:CAS:528:DyaK38Xkt1Cjsbw%3D

    PubMed  CAS  Google Scholar 

  7. AC Sandberg-Nordqvist PA Stahlborn M . Reinecke VP Collins H Hoist Particlevon V Sara (1993) ArticleTitleCharacterization of insulin-like growth␣factor I in human primary brain tumors Cancer Res 33 2475–2478

    Google Scholar 

  8. HN Antoniades T Galanlpoulos J Neville-Golden M Maxwell (1992) ArticleTitleExpression of insulin-like growth factor I, II and their receptor mRNAs in primary human astrocytomas and meningiomas: in vivo studies using in situ hybridization and immunocytochemistry Int J Cancer 50 215–222 Occurrence Handle1370435 Occurrence Handle1:STN:280:DyaK387ht1eltQ%3D%3D

    PubMed  CAS  Google Scholar 

  9. JR Hill N Kuriyama H Kuriyama MA Israel (1999) ArticleTitleMolecular neuropathology of astrocytic brain tumors J Neuro-Oncol 56 439–441 Occurrence Handle1:STN:280:DyaK1M3htlChtg%3D%3D

    CAS  Google Scholar 

  10. R Wechsler-Reya MP Scott (2001) ArticleTitleThe development biology of brain tumors Annu Rev Neurosci 24 385–428 Occurrence Handle11283316 Occurrence Handle10.1146/annurev.neuro.24.1.385 Occurrence Handle1:CAS:528:DC%2BD3MXls1Shs78%3D

    Article  PubMed  CAS  Google Scholar 

  11. JR Testa A Bellacosa (2001) ArticleTitleAKT plays a central role in tumorigenesis Proc Natl Scad Sci USA 98 10983–10985 Occurrence Handle1:CAS:528:DC%2BD3MXnt1yqsrY%3D Occurrence Handle10.1073/pnas.211430998

    Article  CAS  Google Scholar 

  12. SR Datta A Brunet ME Greenberg (1999) ArticleTitleCellular survival: a play in three AKTs Genes Develop 13 2905–2927 Occurrence Handle10579998 Occurrence Handle1:CAS:528:DyaK1MXnvVCltLo%3D

    PubMed  CAS  Google Scholar 

  13. KM Nicholson NG Anderson (2002) ArticleTitleThe protein Kinase B/Akt signaling pathway in human malignancy Cell Signal 14 381–395 Occurrence Handle11882383 Occurrence Handle10.1016/S0898-6568(01)00271-6 Occurrence Handle1:CAS:528:DC%2BD38Xhs1ylsrs%3D

    Article  PubMed  CAS  Google Scholar 

  14. I Vivanco CL Sawyers (2002) ArticleTitleThe phosphotidylinositol-3-kinase-AKT pathway in human cancer Nat Rev Cancer 2 489–501 Occurrence Handle12094235 Occurrence Handle10.1038/nrc839 Occurrence Handle1:CAS:528:DC%2BD38XkvFKltLs%3D

    Article  PubMed  CAS  Google Scholar 

  15. MM Hill BA Hemmings (2002) ArticleTitleInhibition of protein kinase B/Akt: implications for cancer therapy Pharmacol Ther 93 243–253 Occurrence Handle12191616 Occurrence Handle10.1016/S0163-7258(02)00193-6 Occurrence Handle1:CAS:528:DC%2BD38XksVShurg%3D

    Article  PubMed  CAS  Google Scholar 

  16. MP Scheid JR Woodgett (2003) ArticleTitleUnravelling the activation mechanism of protein kinase B/Akt FEBS Lett 546 108–112 Occurrence Handle12829245 Occurrence Handle10.1016/S0014-5793(03)00562-3 Occurrence Handle1:CAS:528:DC%2BD3sXkvVKjs7k%3D

    Article  PubMed  CAS  Google Scholar 

  17. MB Martin TF Franke GE Stoica P Chambon BS Katzenellenbogen BA Stoica MS MoLemore SE Olivo A Stoica (2000) ArticleTitleA role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I Endocrinology 141 4502–4511

    Google Scholar 

  18. RC Musie-Helmericket HL Grimes A Bellacosa SE Malstrom PN Tsichlis N Rosen (1998) ArticleTitleCyclin D expression is controlled post-transcriptionally via a phosphotidylinositol 3-kinase/Akt dependent pathway J Biol Chem 273 29864–29872

    Google Scholar 

  19. LD Mayo DB Donner (2001) ArticleTitleA phosphotidylinositol 3-kinase/Akt pathway promotes translocation of mdm2 from the cytoplasm to the nucleus Proc Natl Acad Sci USA 98 11598–11603 Occurrence Handle11504915 Occurrence Handle10.1073/pnas.181181198 Occurrence Handle1:CAS:528:DC%2BD3MXnt12js7s%3D

    Article  PubMed  CAS  Google Scholar 

  20. SS Kang T Kwon DY Kwon (1999) ArticleTitleAkt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit J Biol Chem 274 13085–13090 Occurrence Handle10224060 Occurrence Handle1:CAS:528:DyaK1MXjtFOlsro%3D

    PubMed  CAS  Google Scholar 

  21. D Kim S Kim H Koh S Yoon A Chung KS Cho J Chung (2001) ArticleTitleAkt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production FASEB J 15 1953–1963 Occurrence Handle11532975 Occurrence Handle10.1096/fj.01-0198com Occurrence Handle1:CAS:528:DC%2BD3MXntlGqt7c%3D

    Article  PubMed  CAS  Google Scholar 

  22. BK Park X Zeng RI Glazer (2001) ArticleTitleAkt induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells Cancer Res 61 7647–7653 Occurrence Handle11606407 Occurrence Handle1:CAS:528:DC%2BD3MXnvFSht74%3D

    PubMed  CAS  Google Scholar 

  23. T Kubiatowski T Jang MB Lachyankar R Salmonsen RR Nabi PJ Quesenberry NS Litofsky AH Ross LD Recht (2001) ArticleTitleAssociation of␣increased phosphotidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas J Neurosurg 95 480–488 Occurrence Handle11565871 Occurrence Handle1:CAS:528:DC%2BD3MXmvFOjurg%3D

    PubMed  CAS  Google Scholar 

  24. BJ Michell JE Griffiths KI Mitchelhill I Rodriguez-Crespo T Tiganis S Bozinovski PR Montellano Particlede BE Kemp RB Pearson (1999) ArticleTitleThe Akt kinase signals directly to endothelial nitric oxide Curr Biol 9 845–848 Occurrence Handle10469573 Occurrence Handle10.1016/S0960-9822(99)80371-6 Occurrence Handle1:CAS:528:DyaK1MXltFChu74%3D

    Article  PubMed  CAS  Google Scholar 

  25. JQ Cheng AK Godwin A Bellacosa T Taguchi TF Franke TC Hamilton PN Tsichilis JR Testa (1992) ArticleTitleAKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas Proc Natl Acad Sci USA 89 9267–9271 Occurrence Handle1409633 Occurrence Handle1:CAS:528:DyaK3sXks12itbs%3D

    PubMed  CAS  Google Scholar 

  26. QZ Yuan M Sun RI Feldman G Wang X Ma C Jiang D Coppola SV Nicosia JQ Cheng (2000) ArticleTitleFrequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer Oncogene 19 2324–2330 Occurrence Handle10822383 Occurrence Handle10.1038/sj.onc.1203598 Occurrence Handle1:CAS:528:DC%2BD3cXjslelsLk%3D

    Article  PubMed  CAS  Google Scholar 

  27. A Bellacosa D deFeo AK Godwin DW Bell JQ Cheng DA Altomare M Wan L Dubeau (1995) ArticleTitleMolecular alterations of the AKT2 oncogenes in ovarian and breast carcinomas Int J Cancer 64 280–285 Occurrence Handle7657393 Occurrence Handle1:CAS:528:DyaK2MXos1Gqsbw%3D

    PubMed  CAS  Google Scholar 

  28. Y Liao R Grobholz U Abel L Trojan MS Michel P Angel D Mayer (2003) ArticleTitleIncrease of AKT/PKB expression correlates with Gleason pattern in human prostate cancer Int J Cancer 107 678–680 Occurrence Handle10.1002/ijc.11471 Occurrence Handle1:CAS:528:DC%2BD3sXoslCjs7s%3D

    Article  CAS  Google Scholar 

  29. MD Ringel N Hayre J Saito B Saunier F Schuppert H Burch V Bernet KD Burman LD Kohn M Saji (2001) ArticleTitleOverexpression and overactivation of Akt in thyroid carcinoma Cancer Res 61 6105–6111 Occurrence Handle11507060 Occurrence Handle1:CAS:528:DC%2BD3MXmt12ktLo%3D

    PubMed  CAS  Google Scholar 

  30. JQ Cheng B Ruggen WM Klein WM Klein G Sonada DA Altomore DK Watson JR Testa (1996) ArticleTitleAmplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA Proc Natl Acad Sci USA 83 3636–3641

    Google Scholar 

  31. T Mukohara S Kudoh S Yamauchi T Kimura N Yoshimura H Kanazawa K Hirata H Wanibuchi S Fukushima K Inoue J Yoshikawa (2003) ArticleTitleExpression of epidermal growth factor receptor (EGFR) and downstream-activated peptides in surgically excised non-small-cell-lung-cancer (NSCLC) Lung Cancer 41 123–130 Occurrence Handle12871775 Occurrence Handle10.1016/S0169-5002(03)00225-3

    Article  PubMed  Google Scholar 

  32. H Nakayama T Ikebe M Beppu K Shirasuna (2001) ArticleTitleHigh expression levels of nuclear factor κB, IkB kinase α, and Akt kinase in squamous cell carcinoma of the oral cavity Cancer 92 3037–3044 Occurrence Handle11753981 Occurrence Handle10.1002/1097-0142(20011215)92:12<3037::AID-CNCR10171>3.0.CO;2-# Occurrence Handle1:CAS:528:DC%2BD38XjvVejsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  33. M Sun G Wang JE Paciga RI Feldman ZQ Yuan X Ma SA Shelly R Jove PN Tsichilis SV Nicosia JQ Cheng (2001) ArticleTitleAKT1/PKBα kinase is frequent elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells Am J Pathol 159 431–437 Occurrence Handle11485901 Occurrence Handle1:CAS:528:DC%2BD3MXms1Wisb8%3D

    PubMed  CAS  Google Scholar 

  34. G Choe S Horvath TF Cloughsey K Crowsby D Seligson A Palotie L Inge BL Smith CL Sawyers PS Mischel (2003) ArticleTitleAnalysis of the phosphotidylinositol−3’-kinase signaling pathway in glioblastoma patients in vivo Cancer Res 63 2742–2746 Occurrence Handle12782577 Occurrence Handle1:CAS:528:DC%2BD3sXkt1aju7w%3D

    PubMed  CAS  Google Scholar 

  35. RP Ermoian CS Furniss KR Lamborn D Basila MS Berger AR Gottschalk MK Nicholas D Stokoe DA Haas-Kogan (2002) ArticleTitleDysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival Clin Cancer Res 8 1100–1106 Occurrence Handle12006525 Occurrence Handle1:CAS:528:DC%2BD38XksVSqu7o%3D

    PubMed  CAS  Google Scholar 

  36. J Schlegel G Piontek HD Mennel (2002) ArticleTitleActivation of the anti-apoptotic Akt/protein kinase B pathway in human malignant gliomas in vivo Anticancer Res 22 2837–2840 Occurrence Handle12530006 Occurrence Handle1:CAS:528:DC%2BD3sXosl2juw%3D%3D

    PubMed  CAS  Google Scholar 

  37. Y Sonada T Ozawa KD Aldape DF Deen MS Berger RO Pieper (2001) ArticleTitleAkt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma Cancer Res 61 6674–6678

    Google Scholar 

  38. P Pu X Liu A Liu JL Cui YT Zhang (2000) ArticleTitleInhibitory effects of antisense epidermal growth factor receptor RNA on the proliferation of rat C6 gliom cells in vitro and in vivo J Neurosurg 92 132–139 Occurrence Handle10616092 Occurrence Handle1:CAS:528:DC%2BD3cXmsVOgtw%3D%3D

    PubMed  CAS  Google Scholar 

  39. TE VanMeter HK Roopai MM Kibble HL Fillmore WC Broaddus GJ Pilkington (2001) ArticleTitleThe role of matrix metalloproteinases genes in glioma cell invasion: codependent and interactive proteolysis J Neuro-Oncol 53 213–215 Occurrence Handle10.1023/A:1012280925031 Occurrence Handle1:STN:280:DC%2BD3MnmvFyqsQ%3D%3D

    Article  CAS  Google Scholar 

  40. JH Uhm NP Dooley JG Villemure VW Yong (1997) ArticleTitleGlioma invasion in vitro: role of matrix metalloproteinases Can J Neurol Sci 24 3–15 Occurrence Handle9043741 Occurrence Handle1:STN:280:DyaK2s7ps1KmsA%3D%3D

    PubMed  CAS  Google Scholar 

  41. DK Binder MS Berger (2002) ArticleTitleProteases and the biology of glioma cell invasion J Neuro-Oncol 56 149–158 Occurrence Handle10.1023/A:1014566604005

    Article  Google Scholar 

  42. M Pekney C Eliasson CL Chien LG Kindblom R Liem A Hamberger C Betsholtz (1998) ArticleTitleGFAP-deficient astrocytes are capable of stellation in vitro when cocultured with neurons and exhibits a reduced amounts of intermediate filaments and an increased cell saturation density Exp Cell Res 239 332–343

    Google Scholar 

  43. M Toda M Miura H Asou S Toya K Uyemura (1994) ArticleTitleCell growth suppression of astrocytoma C6 cells by glial fibrillary acidic protein CDNA transfection J Neurochem 63 1975–1978 Occurrence Handle7931355 Occurrence Handle1:CAS:528:DyaK2cXmsFaktrw%3D

    PubMed  CAS  Google Scholar 

  44. Y Narita M Nagane K Mishima HJS Huang FB Furnari WK Cavenee (2002) ArticleTitleMutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphotidylinositol 3-K/Akt pathway in glioblastomas Cancer Res 62 6764–6769 Occurrence Handle12438278 Occurrence Handle1:CAS:528:DC%2BD38XovFOksbg%3D

    PubMed  CAS  Google Scholar 

  45. NR Leslie CP Downes (2002) ArticleTitlePTEN: The down side of PI3-Kinase signaling Cell Signal 14 285–295 Occurrence Handle11858936 Occurrence Handle10.1016/S0898-6568(01)00234-0 Occurrence Handle1:CAS:528:DC%2BD38Xhtleqtbc%3D

    Article  PubMed  CAS  Google Scholar 

  46. D Haas-Kogan N Shalev M Wong G Mills G Yount D Stokoe (1998) ArticleTitleProtein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC Curr Biol 8 1195–1198 Occurrence Handle9799739 Occurrence Handle1:CAS:528:DyaK1cXntFWgsbg%3D Occurrence Handle10.1016/S0960-9822(07)00493-9

    Article  PubMed  CAS  Google Scholar 

  47. ML Sulis Parsons R Parsons (2003) ArticleTitlePTEN: from pathology to biology Trends Cell Biol 13 478–483

    Google Scholar 

  48. AE Wakeling SP Guy JR Woodburn SE Ashtou BJ Curry AJ Burker KH Gibson (2002) ArticleTitleZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy Cancer Res 62 5749–5754 Occurrence Handle12384534 Occurrence Handle1:CAS:528:DC%2BD38XotFyktr8%3D

    PubMed  CAS  Google Scholar 

  49. IW Tremont-Lukats MR Gilbert (2003) ArticleTitleAdvances in molecular therapies in patients with brain tumors Cancer Control 10 125–137 Occurrence Handle12712007

    PubMed  Google Scholar 

  50. J Trojan BK Blossey TR Johnson SD Rudin M Tykocinski J Ilan J Ilan (1992) ArticleTitleLoss of tumorigenicity of rat glioblastoma directed by episome-based antisense cDNA transcription of insulin-like growth factor I Proc Natl Acad Sci USA 89 4874–4878 Occurrence Handle1594587 Occurrence Handle1:CAS:528:DyaK38XksVGlt7c%3D

    PubMed  CAS  Google Scholar 

  51. J Trojan TR Johnson SD Rudin J Ilan ML Tykocinski J Ilan (1993) ArticleTitleTreatment and prevention of rat glioblastoma by immunogenic C6 cells expressing antisense insulin-like growth factor I RNA Science 259 94–97 Occurrence Handle8418502 Occurrence Handle1:CAS:528:DyaK3sXptl2itw%3D%3D

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, People’s Republic of China

    Peiyu Pu, Chunsheng Kang & Jie Li

  2. William T. Gossett Neurology Laboratories, Department of Neurology, Henry Ford Health System, Detroit, MI, USA

    Hao Jiang

  3. Department of Pathology, H Lee Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, FL, USA

    Jinquan Cheng

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Correspondence to Peiyu Pu.

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Pu, P., Kang, C., Li, J. et al. The Effects of Antisense AKT2 RNA on the Inhibition of Malignant Glioma Cell Growth in vitro and in vivo . J Neurooncol 76, 1–11 (2006). https://doi.org/10.1007/s11060-005-3029-3

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