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

Mender,Ilgen; Senturk,Serif; Ozgunes,Nuriman; Akcali,K.  Can; Kletsas,Dimitris; Gryaznov,Sergei; Can,Alp; Shay,Jerry  W.; Dikmen,Z.   Gunnur

doi:10.3892/ijo.2013.1865

May 2013 Volume 42 Issue 5

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May 2013 Volume 42 Issue 5

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Article

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

Authors:
- Ilgen Mender
- Serif Senturk
- Nuriman Ozgunes
- K. Can Akcali
- Dimitris Kletsas
- Sergei Gryaznov
- Alp Can
- Jerry W. Shay
- Z. Gunnur Dikmen
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Affiliations: Department of Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey, Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey, Laboratory of Cell Proliferation and Ageing, Institute of Biology, National Centre for Scientific Research ‘Demokritos’, Athens, Greece, Geron Corporation, Menlo Park, CA, USA, Department of Histology and Embryology, Faculty of Medicine, Ankara University, Ankara, Turkey, University of Texas Southwestern Medical Center, Dallas, TX, USA
Pages: 1709-1715
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Published online on: March 27, 2013

https://doi.org/10.3892/ijo.2013.1865
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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.

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1.	Dempke WC, Suto T and Reck M: Targeted therapies for non-small cell lung cancer. Lung Cancer. 67:257–274. 2010. View Article : Google Scholar : PubMed/NCBI
2.	Tassinari D, Scarpi E, Sartori S, Tamburini E, Santelmo C, Tombesi P and Lazzari-Agli L: Second-line treatments in non-small cell lung cancer. A systematic review of literature and metaanalysis of randomized clinical trials. Chest. 135:1596–1609. 2009. View Article : Google Scholar : PubMed/NCBI
3.	Blackburn EH: Switching and signaling at the telomere. Cell. 106:661–673. 2001. View Article : Google Scholar : PubMed/NCBI
4.	Greider CW and Blackburn EH: Telomeres, telomerase and cancer. Sci Am. 274:92–97. 1996. View Article : Google Scholar
5.	Hiyama E and Hiyama K: Telomere and telomerase in stem cells. Br J Cancer. 96:1020–1024. 2007. View Article : Google Scholar : PubMed/NCBI
6.	Collins K and Mitchell JR: Telomerase in the human organism. Oncogene. 21:564–579. 2002. View Article : Google Scholar : PubMed/NCBI
7.	Blasco MA: Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 6:611–622. 2005. View Article : Google Scholar : PubMed/NCBI
8.	Wai LK: Telomeres, telomerase and tumorigenesis - a review. Med Gen Med. 6:192004.PubMed/NCBI
9.	Shay JW and Wright WE: Telomerase: a target for cancer therapeutics. Cancer Cell. 2:257–265. 2002. View Article : Google Scholar : PubMed/NCBI
10.	Harley CB: Telomerase and cancer therapeutics. Nat Rev Cancer. 8:167–179. 2008. View Article : Google Scholar
11.	Herbert BS, Gellert GC, Hochreiter A, et al: Lipid modification of GRN163, an N3′→P5′ thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene. 24:5262–5268. 2005.PubMed/NCBI
12.	Gryaznov SM: Oligonucleotide N3′→P5′ phosphoramidates and thio-phoshoramidates as potential therapeutic agents. Chem Biodivers. 7:477–493. 2010.
13.	Dikmen ZG, Gellert GC, Jackson S, et al: In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor. Cancer Res. 65:7866–7873. 2005.PubMed/NCBI
14.	Jackson SR, Zhu CH, Paulson V, et al: Antiadhesive effects of GRN163L - an oligonucleotide N3′→P5′ thio-phosphoramidate targeting telomerase. Cancer Res. 67:1121–1129. 2007.PubMed/NCBI
15.	Svitkina T: Imaging cytoskeleton components by electron microscopy. Methods Mol Biol. 586:187–206. 2009. View Article : Google Scholar : PubMed/NCBI
16.	Pećina-Slaus N: Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int. 3:172003.PubMed/NCBI
17.	Qian Q, Wang Q, Zhan P, Peng L, Wei SZ, Shi Y and Song Y: The role of matrix metalloproteinase 2 on the survival of patients with non-small cell lung cancer: a systematic review with meta-analysis. Cancer Invest. 28:661–669. 2010. View Article : Google Scholar : PubMed/NCBI
18.	Goldblatt EM, Gentry ER, Fox MJ, Gryaznov SM, Shen C and Herbert BS: The telomerase template antagonist GRN163L alters MDA-MB-231 breast cancer cell morphology, inhibits growth, and augments the effects of paclitaxel. Mol Cancer Ther. 8:2027–2035. 2009. View Article : Google Scholar : PubMed/NCBI
19.	Shin IJ, Ahn YT, Kim Y, Kim JM and An WG: Actin disruption agents induce phosphorylation of histone H2AX in human breast adenocarcinoma MCF-7 cells. Oncol Rep. 25:1313–1319. 2011.PubMed/NCBI
20.	Perez EA: Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Ther. 8:2086–2095. 2009. View Article : Google Scholar : PubMed/NCBI
21.	Hojilla CV, Mohammed FF and Khokha R: Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development. Br J Cancer. 89:1817–1821. 2003. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

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

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