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Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells
Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a bette...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584138/ https://www.ncbi.nlm.nih.gov/pubmed/28881569 http://dx.doi.org/10.18632/oncotarget.18970 |
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author | Do, Thuy-Vy Hirst, Jeff Hyter, Stephen Roby, Katherine F. Godwin, Andrew K. |
author_facet | Do, Thuy-Vy Hirst, Jeff Hyter, Stephen Roby, Katherine F. Godwin, Andrew K. |
author_sort | Do, Thuy-Vy |
collection | PubMed |
description | Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a better understanding of signaling pathways important for ovarian cancer progression. Aurora A kinase (AURKA) plays an important role in ovarian cancer progression by mediating mitosis and chromosomal instability. In the current study, we investigated the role of AURKA in regulating the DNA damage response and DNA repair in ovarian carcinoma cells. We discovered that AURKA modulated the expression and activity of PARP, a crucial mediator of DNA repair that is a target of therapeutic interest for the treatment of ovarian and other cancers. Further, specific inhibition of AURKA activity with the small molecule inhibitor, alisertib, stimulated the non-homologous end-joining (NHEJ) repair pathway by elevating DNA-PKcs activity, a catalytic subunit required for double-strand break (DSB) repair, as well as decreased the expression of PARP and BRCA1/2, which are required for high-fidelity homologous recombination-based DNA repair. Further, AURKA inhibition stimulates error-prone NHEJ repair of DNA double-strand breaks with incompatible ends. Consistent with in vitro findings, alisertib treatment increased phosphorylated DNA-PKcs(pDNA-PKcs(T2609)) and decreased PARP levels in vivo. Collectively, these results reveal new non-mitotic functions for AURKA in the regulation of DNA repair, which may inform of new therapeutic targets and strategies for treating ovarian cancer. |
format | Online Article Text |
id | pubmed-5584138 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-55841382017-09-06 Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells Do, Thuy-Vy Hirst, Jeff Hyter, Stephen Roby, Katherine F. Godwin, Andrew K. Oncotarget Priority Research Paper Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a better understanding of signaling pathways important for ovarian cancer progression. Aurora A kinase (AURKA) plays an important role in ovarian cancer progression by mediating mitosis and chromosomal instability. In the current study, we investigated the role of AURKA in regulating the DNA damage response and DNA repair in ovarian carcinoma cells. We discovered that AURKA modulated the expression and activity of PARP, a crucial mediator of DNA repair that is a target of therapeutic interest for the treatment of ovarian and other cancers. Further, specific inhibition of AURKA activity with the small molecule inhibitor, alisertib, stimulated the non-homologous end-joining (NHEJ) repair pathway by elevating DNA-PKcs activity, a catalytic subunit required for double-strand break (DSB) repair, as well as decreased the expression of PARP and BRCA1/2, which are required for high-fidelity homologous recombination-based DNA repair. Further, AURKA inhibition stimulates error-prone NHEJ repair of DNA double-strand breaks with incompatible ends. Consistent with in vitro findings, alisertib treatment increased phosphorylated DNA-PKcs(pDNA-PKcs(T2609)) and decreased PARP levels in vivo. Collectively, these results reveal new non-mitotic functions for AURKA in the regulation of DNA repair, which may inform of new therapeutic targets and strategies for treating ovarian cancer. Impact Journals LLC 2017-07-05 /pmc/articles/PMC5584138/ /pubmed/28881569 http://dx.doi.org/10.18632/oncotarget.18970 Text en Copyright: © 2017 Do et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Priority Research Paper Do, Thuy-Vy Hirst, Jeff Hyter, Stephen Roby, Katherine F. Godwin, Andrew K. Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells |
title | Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells |
title_full | Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells |
title_fullStr | Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells |
title_full_unstemmed | Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells |
title_short | Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells |
title_sort | aurora a kinase regulates non-homologous end-joining and poly(adp-ribose) polymerase function in ovarian carcinoma cells |
topic | Priority Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584138/ https://www.ncbi.nlm.nih.gov/pubmed/28881569 http://dx.doi.org/10.18632/oncotarget.18970 |
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