Imetelstat (a telomerase antagonist) exerts off target effects on the cytoskeleton
Author
Mender I.
Senturk, S.
Ozgunes, N.
Can Akcali, K.
Kletsas, D.
Gryaznov, S.
Can, A.
Shay J.W.
Dikmen, Z.G.
Date
2013Source Title
International Journal of Oncology
Print ISSN
10196439
Volume
42
Issue
5
Pages
1709 - 1715
Language
English
Type
ArticleItem Usage Stats
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Show full item recordAbstract
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 adhesionE-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