Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines
Abstract 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; ho...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-10-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12931-019-1194-8 |
| _version_ | 1828531976329494528 |
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| author | Ningbo Liu Yong Antican Wang Yunguang Sun Jeffrey Ecsedy Jifeng Sun Xue Li Ping Wang |
| author_facet | Ningbo Liu Yong Antican Wang Yunguang Sun Jeffrey Ecsedy Jifeng Sun Xue Li Ping Wang |
| author_sort | Ningbo Liu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-11T22:46:25Z |
| format | Article |
| id | doaj.art-1207ddcb41364241abe187204ed5ecc4 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-12-11T22:46:25Z |
| publishDate | 2019-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-1207ddcb41364241abe187204ed5ecc42022-12-22T00:47:36ZengBMCRespiratory Research1465-993X2019-10-0120111510.1186/s12931-019-1194-8Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell linesNingbo Liu0Yong Antican Wang1Yunguang Sun2Jeffrey Ecsedy3Jifeng Sun4Xue Li5Ping Wang6Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of CancerBiomed Innovation Center of Yehoo Group Co. Ltd.Department of Radiation Oncology, Thomas Jefferson UniversityTakeda Pharmaceuticals International CoDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of CancerDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of CancerDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of CancerAbstract 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.http://link.springer.com/article/10.1186/s12931-019-1194-8AURKAMLN8237AlisertibRadiosensitivityLung cancerP53 |
| spellingShingle | Ningbo Liu Yong Antican Wang Yunguang Sun Jeffrey Ecsedy Jifeng Sun Xue Li Ping Wang Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines Respiratory Research AURKA MLN8237 Alisertib Radiosensitivity Lung cancer P53 |
| 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 | AURKA MLN8237 Alisertib Radiosensitivity Lung cancer P53 |
| url | http://link.springer.com/article/10.1186/s12931-019-1194-8 |
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