Abstract
Exposure of the telomere overhang acts as a DNA damage signal, and exogenous administration of an 11-base oligonucleotide homologous to the 3'-telomere overhang sequence (T-oligo) mimics the effects of overhang exposure by inducing senescence and cell death in non-small cell lung cancer (NSCLC) cells, but not in normal bronchial epithelial cells. T-oligo-induced decrease in cellular proliferation in NSCLC is likely directed through both p53 and its homolog, p73, with subsequent induction of senescence and expression of senescence-associated proteins, p21, p33(ING), and p27(Kip1) both in vivo and in vitro. Additionally, T-oligo decreases tumor size and inhibits angiogenesis through decreased VEGF signaling and increased TSP-1 expression.
Keywords:
Angiogenesis; Apoptosis; Lung cancer; Senescence; Telomere overhang; p53.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Bronchi / pathology
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Carcinoma, Non-Small-Cell Lung / genetics*
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Cell Line, Tumor
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Cell Proliferation
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Cellular Senescence
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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DNA Damage*
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Epithelial Cells / cytology
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Gene Expression Regulation, Neoplastic
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Genetic Predisposition to Disease*
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Humans
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Inhibitor of Growth Protein 1
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Neovascularization, Pathologic*
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Nuclear Proteins / metabolism
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Oligonucleotides / genetics
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Signal Transduction
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Telomere / ultrastructure*
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Tumor Suppressor Proteins / metabolism
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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ING1 protein, human
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Inhibitor of Growth Protein 1
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Oligonucleotides
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SPZ1 protein, human
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Tumor Suppressor Proteins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Cyclin-Dependent Kinase Inhibitor p27