Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Inhibition of Aurora A enhances radiosensitivity in selected lung cancer cell lines. Respir Res 2019 Oct 23;20(1):230

Date

10/28/2019

Pubmed ID

31647033

Pubmed Central ID

PMC6813099

DOI

10.1186/s12931-019-1194-8

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.

Author List

Liu N, Wang YA, Sun Y, Ecsedy J, Sun J, Li X, Wang P

Author

Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Aurora Kinase A
Azepines
Biomarkers, Tumor
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Female
Humans
Lung Neoplasms
Mice
Mice, Nude
Pyrimidines
Radiation Tolerance
Retrospective Studies
Xenograft Model Antitumor Assays
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a