Targeting homologous recombination and telomerase in Barrett’s adenocarcinoma: Impact on telomere maintenance, genomic instability, and tumor growth
View/ Open
Author
Lu, Renquan
Pal, Jagannath
Buon, Leutz
Nanjappa, Puru
Guo, Lin
Yu, Min
Gryaznov, Sergei
Shammas, Masood A.
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1038/onc.2013.103Metadata
Show full item recordCitation
Lu, R., J. Pal, L. Buon, P. Nanjappa, J. Shi, M. Fulciniti, Y. Tai, et al. 2014. “Targeting homologous recombination and telomerase in Barrett’s adenocarcinoma: Impact on telomere maintenance, genomic instability, and tumor growth.” Oncogene 33 (12): 1495-1505. doi:10.1038/onc.2013.103. http://dx.doi.org/10.1038/onc.2013.103.Abstract
Homologous recombination (HR), a mechanism to accurately repair DNA in normal cells, is deregulated in cancer. Elevated/deregulated HR is implicated in genomic instability and telomere maintenance, which are critical lifelines of cancer cells. We have previously shown that HR activity is elevated and significantly contributes to genomic instability in BAC. The purpose of this study was to evaluate therapeutic potential of HR inhibition, alone and in combination with telomerase inhibition, in BAC. We demonstrate that telomerase inhibition in BAC cells increases HR activity, RAD51 expression, and association of RAD51 to telomeres. Suppression of HR leads to shorter telomeres as well as markedly reduced genomic instability in BAC cells over time. Combination of HR suppression (whether transgenic or chemical) with telomerase inhibition, causes a significant increase in telomere attrition and apoptotic death in all BAC cell lines tested, relative to either treatment alone. A subset of treated cells also stain positive for β-galactosidase, indicating senescence. The combined treatment is also associated with decline in S-phase and a strong G2/M arrest, indicating massive telomere attrition. In a subcutaneous tumor model, the combined treatment resulted in the smallest tumors, which were even smaller (P=0.001) than those resulted from either treatment alone. Even the tumors removed from these mice had significantly reduced telomeres and evidence of apoptosis. We therefore conclude that although telomeres are elongated by telomerase, elevated RAD51/HR assist in their maintenance/stabilization in BAC cells. Telomerase inhibitor prevents telomere elongation but induces RAD51/HR, which contribute to telomere maintenance/stabilization and prevention of apoptosis, reducing the efficacy of treatment. Combining HR inhibition with telomerase, makes telomeres more vulnerable to degradation and significantly increases/expedites their attrition, leading to apoptosis. We therefore demonstrate that a therapy, targeting HR and telomerase, has potential to prevent both the tumor growth and genomic evolution in BAC.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940666/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:12987413
Collections
- HMS Scholarly Articles [17918]
Contact administrator regarding this item (to report mistakes or request changes)