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Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines
BACKGROUND: In mammalian cells, Aurora serine/threonine kinases (Aurora A, B, and C) are expressed in a cell cycle-dependent fashion as key mitotic regulators required for the maintenance of chromosomal stability. Aurora-A (AURKA) has been proven to be an oncogene in a variety of cancers; however, w...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813099/ https://www.ncbi.nlm.nih.gov/pubmed/31647033 http://dx.doi.org/10.1186/s12931-019-1194-8 |
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author | Liu, Ningbo Wang, Yong Antican Sun, Yunguang Ecsedy, Jeffrey Sun, Jifeng Li, Xue Wang, Ping |
author_facet | Liu, Ningbo Wang, Yong Antican Sun, Yunguang Ecsedy, Jeffrey Sun, Jifeng Li, Xue Wang, Ping |
author_sort | Liu, Ningbo |
collection | PubMed |
description | BACKGROUND: In mammalian cells, Aurora serine/threonine kinases (Aurora A, B, and C) are expressed in a cell cycle-dependent fashion as key mitotic regulators required for the maintenance of chromosomal stability. Aurora-A (AURKA) has been proven to be an oncogene in a variety of cancers; however, whether its expression relates to patient survival and the association with radiotherapy remains unclear in non-small cell lung cancer (NSCLC). METHODS: Here, we first analyzed AURKA expression in 63 NSCLC tumor samples by immunohistochemistry (IHC) and used an MTS assay to compare cell survival by targeting AURKA with MLN8237 (Alisertib) in H460 and HCC2429 (P53-competent), and H1299 (P53-deficient) cell lines. The radiosensitivity of MLN8237 was further evaluated by clonogenic assay. Finally, we examined the effect of combining radiation and AURKA inhibition in vivo with a xenograft model and explored the potential mechanism. RESULTS: We found that increased AURKA expression correlated with decreased time to progression and overall survival (p = 0.0447 and 0.0096, respectively). AURKA inhibition using 100 nM MLN8237 for 48 h decreases cell growth in a partially P53-dependent manner, and the survival rates of H460, HCC2429, and H1299 cells were 56, 50, and 77%, respectively. In addition, the survival of H1299 cells decreased 27% after ectopic restoration of P53 expression, and the radiotherapy enhancement was also influenced by P53 expression (DER H460 = 1.33; HCC2429 = 1.35; H1299 = 1.02). Furthermore, tumor growth of H460 was delayed significantly in a subcutaneous mouse model exposed to both MLN8237 and radiation. CONCLUSIONS: Taken together, our results confirmed that the expression of AURKA correlated with decreased NSCLC patient survival, and it might be a promising inhibition target when combined with radiotherapy, especially for P53-competent lung cancer cells. Modulation of P53 function could provide a new option for reversing cell resistance to the AURKA inhibitor MLN8237, which deserves further investigation. |
format | Online Article Text |
id | pubmed-6813099 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-68130992019-10-30 Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines Liu, Ningbo Wang, Yong Antican Sun, Yunguang Ecsedy, Jeffrey Sun, Jifeng Li, Xue Wang, Ping Respir Res Research BACKGROUND: In mammalian cells, Aurora serine/threonine kinases (Aurora A, B, and C) are expressed in a cell cycle-dependent fashion as key mitotic regulators required for the maintenance of chromosomal stability. Aurora-A (AURKA) has been proven to be an oncogene in a variety of cancers; however, whether its expression relates to patient survival and the association with radiotherapy remains unclear in non-small cell lung cancer (NSCLC). METHODS: Here, we first analyzed AURKA expression in 63 NSCLC tumor samples by immunohistochemistry (IHC) and used an MTS assay to compare cell survival by targeting AURKA with MLN8237 (Alisertib) in H460 and HCC2429 (P53-competent), and H1299 (P53-deficient) cell lines. The radiosensitivity of MLN8237 was further evaluated by clonogenic assay. Finally, we examined the effect of combining radiation and AURKA inhibition in vivo with a xenograft model and explored the potential mechanism. RESULTS: We found that increased AURKA expression correlated with decreased time to progression and overall survival (p = 0.0447 and 0.0096, respectively). AURKA inhibition using 100 nM MLN8237 for 48 h decreases cell growth in a partially P53-dependent manner, and the survival rates of H460, HCC2429, and H1299 cells were 56, 50, and 77%, respectively. In addition, the survival of H1299 cells decreased 27% after ectopic restoration of P53 expression, and the radiotherapy enhancement was also influenced by P53 expression (DER H460 = 1.33; HCC2429 = 1.35; H1299 = 1.02). Furthermore, tumor growth of H460 was delayed significantly in a subcutaneous mouse model exposed to both MLN8237 and radiation. CONCLUSIONS: Taken together, our results confirmed that the expression of AURKA correlated with decreased NSCLC patient survival, and it might be a promising inhibition target when combined with radiotherapy, especially for P53-competent lung cancer cells. Modulation of P53 function could provide a new option for reversing cell resistance to the AURKA inhibitor MLN8237, which deserves further investigation. BioMed Central 2019-10-23 2019 /pmc/articles/PMC6813099/ /pubmed/31647033 http://dx.doi.org/10.1186/s12931-019-1194-8 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Liu, Ningbo Wang, Yong Antican Sun, Yunguang Ecsedy, Jeffrey Sun, Jifeng Li, Xue Wang, Ping Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines |
title | Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines |
title_full | Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines |
title_fullStr | Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines |
title_full_unstemmed | Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines |
title_short | Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines |
title_sort | inhibition of aurora a enhances radiosensitivity in selected lung cancer cell lines |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813099/ https://www.ncbi.nlm.nih.gov/pubmed/31647033 http://dx.doi.org/10.1186/s12931-019-1194-8 |
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