Non-small cell lung cancer is susceptible to induction of DNA damage responses and inhibition of angiogenesis by telomere overhang oligonucleotides

Neelu Puri; Ryan T Pitman; Richard E Mulnix; Terrianne Erickson; Audra N Iness; Connie Vitali; Yutong Zhao; Ravi Salgia

doi:10.1016/j.canlet.2013.09.010

Non-small cell lung cancer is susceptible to induction of DNA damage responses and inhibition of angiogenesis by telomere overhang oligonucleotides

Cancer Lett. 2014 Feb 1;343(1):14-23. doi: 10.1016/j.canlet.2013.09.010. Epub 2013 Sep 14.

Authors

Neelu Puri¹, Ryan T Pitman², Richard E Mulnix², Terrianne Erickson², Audra N Iness², Connie Vitali³, Yutong Zhao⁴, Ravi Salgia⁵

Affiliations

¹ Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL, United States. Electronic address: neelupur@uic.edu.
² Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL, United States.
³ Department of Pathology, University of Illinois College of Medicine, Rockford, IL, United States.
⁴ Department of Medicine, Division of Pulmonary, Allergy, Critical Care, University of Pittsburgh, Pittsburgh, PA, United States.
⁵ Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, United States.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
Bronchi / pathology
Carcinoma, Non-Small-Cell Lung / genetics*
Cell Line, Tumor
Cell Proliferation
Cellular Senescence
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
DNA Damage*
Epithelial Cells / cytology
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease*
Humans
Inhibitor of Growth Protein 1
Intracellular Signaling Peptides and Proteins / metabolism
Male
Mice
Mice, Nude
Neoplasm Transplantation
Neovascularization, Pathologic*
Nuclear Proteins / metabolism
Oligonucleotides / genetics
Signal Transduction
Telomere / ultrastructure*
Tumor Suppressor Proteins / metabolism
Vascular Endothelial Growth Factor A / metabolism

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
ING1 protein, human
Inhibitor of Growth Protein 1
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
Oligonucleotides
SPZ1 protein, human
Tumor Suppressor Proteins
VEGFA protein, human
Vascular Endothelial Growth Factor A
Cyclin-Dependent Kinase Inhibitor p27

Abstract

Publication types

MeSH terms

Substances

Grants and funding