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dc.contributor.authorMender I.en_US
dc.contributor.authorSenturk, S.en_US
dc.contributor.authorOzgunes, N.en_US
dc.contributor.authorCan Akcali, K.en_US
dc.contributor.authorKletsas, D.en_US
dc.contributor.authorGryaznov, S.en_US
dc.contributor.authorCan, A.en_US
dc.contributor.authorShay J.W.en_US
dc.contributor.authorDikmen, Z.G.en_US
dc.date.accessioned2016-02-08T09:39:04Z
dc.date.available2016-02-08T09:39:04Z
dc.date.issued2013en_US
dc.identifier.issn10196439
dc.identifier.urihttp://hdl.handle.net/11693/20982
dc.description.abstractTelomerase 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.en_US
dc.language.isoEnglishen_US
dc.source.titleInternational Journal of Oncologyen_US
dc.relation.isversionofhttp://dx.doi.org/10.3892/ijo.2013.1865en_US
dc.subjectCell adhesionen_US
dc.subjectE-cadherinen_US
dc.subjectGRN163Len_US
dc.subjectMatrix metalloproteinase-2en_US
dc.subjectNon-small cell lung canceren_US
dc.subjectactinen_US
dc.subjectalpha actininen_US
dc.subjectcyclin D1en_US
dc.subjectcyclin dependent kinase 4en_US
dc.subjectcyclin dependent kinase 6en_US
dc.subjectcyclophilin Aen_US
dc.subjectF actinen_US
dc.subjectgelatinase Aen_US
dc.subjectimetelstaten_US
dc.subjectmessenger RNAen_US
dc.subjecttelomeraseen_US
dc.subjecttubulinen_US
dc.subjectuvomorulinen_US
dc.subjectarticleen_US
dc.subjectcell adhesionen_US
dc.subjectcell proliferationen_US
dc.subjectcytoskeletonen_US
dc.subjectdown regulationen_US
dc.subjectdrug efficacyen_US
dc.subjectenzyme activityen_US
dc.subjectG1 phase cell cycle checkpointen_US
dc.subjecthumanen_US
dc.subjecthuman cellen_US
dc.subjectlung non small cell canceren_US
dc.subjectnucleotide sequenceen_US
dc.subjectpriority journalen_US
dc.subjectprotein expressionen_US
dc.subjectprotein structureen_US
dc.subjectAnimalsen_US
dc.subjectCarcinoma, Non-Small-Cell Lungen_US
dc.subjectClinical Trials as Topicen_US
dc.subjectCytoskeletonen_US
dc.subjectGene Expression Regulation, Neoplasticen_US
dc.subjectHumansen_US
dc.subjectIndolesen_US
dc.subjectLung Neoplasmsen_US
dc.subjectMatrix Metalloproteinase 2en_US
dc.subjectMiceen_US
dc.subjectNiacinamideen_US
dc.subjectTelomeraseen_US
dc.subjectTelomere Homeostasisen_US
dc.titleImetelstat (a telomerase antagonist) exerts off target effects on the cytoskeletonen_US
dc.typeArticleen_US
dc.departmentDepartment of Molecular Biology and Genetics
dc.citation.spage1709en_US
dc.citation.epage1715en_US
dc.citation.volumeNumber42en_US
dc.citation.issueNumber5en_US
dc.identifier.doi10.3892/ijo.2013.1865en_US


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