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      Imetelstat (a telomerase antagonist) exerts off target effects on the cytoskeleton

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      Author
      Mender I.
      Senturk, S.
      Ozgunes, N.
      Can Akcali, K.
      Kletsas, D.
      Gryaznov, S.
      Can, A.
      Shay J.W.
      Dikmen, Z.G.
      Date
      2013
      Source Title
      International Journal of Oncology
      Print ISSN
      10196439
      Volume
      42
      Issue
      5
      Pages
      1709 - 1715
      Language
      English
      Type
      Article
      Item Usage Stats
      154
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      118
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      Abstract
      Telomerase is a cellular ribonucleoprotein reverse transcriptase that plays a crucial role in telomere maintenance. This enzyme is expressed in approximately 90% of human tumors, but not in the majority of normal somatic cells. Imetelstat sodium (GRN163L), is a 13-mer oligonucleotide N3'→P5' thio-phosphoramidate lipid conjugate, which represents the latest generation of telomerase inhibitors targeting the template region of the human functional telomerase RNA (hTR) subunit. In preclinical trials, this compound has been found to inhibit telomerase activity in multiple cancer cell lines, as well as in vivo xenograft mouse models. Currently, GRN163L is being investigated in several clinical trials, including a phase II human non small cell lung cancer clinical trial, in a maintenance setting following standard doublet chemotherapy. In addition to the inhibition of telomerase activity in cancer cell lines, GRN163L causes morphological cell rounding changes, independent of hTR expression or telomere length. This leads to the loss of cell adhesion properties; however, the mechanism underlying this effect is not yet fully understood. In the present study, we observed that GRN163L treatment leads to the loss of adhesion in A549 lung cancer cells, due to decreased E-cadherin expression, leading to the disruption of the cytoskeleton through the alteration of actin, tubulin and intermediate filament organization. Consequently, the less adherent cancer cells initially cease to proliferate and are arrested in the G1 phase of the cell cycle, accompanied by decreased matrix metalloproteinase-2 (MMP-2) expression. These effects of GRN163L are independent of its telomerase catalytic activity and may increase the therapeutic efficacy of GRN163L by decreasing the adhesion, proliferation and metastatic potential of cancer cells in vivo.
      Keywords
      Cell adhesion
      E-cadherin
      GRN163L
      Matrix metalloproteinase-2
      Non-small cell lung cancer
      actin
      alpha actinin
      cyclin D1
      cyclin dependent kinase 4
      cyclin dependent kinase 6
      cyclophilin A
      F actin
      gelatinase A
      imetelstat
      messenger RNA
      telomerase
      tubulin
      uvomorulin
      article
      cell adhesion
      cell proliferation
      cytoskeleton
      down regulation
      drug efficacy
      enzyme activity
      G1 phase cell cycle checkpoint
      human
      human cell
      lung non small cell cancer
      nucleotide sequence
      priority journal
      protein expression
      protein structure
      Animals
      Carcinoma, Non-Small-Cell Lung
      Clinical Trials as Topic
      Cytoskeleton
      Gene Expression Regulation, Neoplastic
      Humans
      Indoles
      Lung Neoplasms
      Matrix Metalloproteinase 2
      Mice
      Niacinamide
      Telomerase
      Telomere Homeostasis
      Permalink
      http://hdl.handle.net/11693/20982
      Published Version (Please cite this version)
      http://dx.doi.org/10.3892/ijo.2013.1865
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