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; 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.

• Authors: Ningbo Liu, Yong Antican Wang, Yunguang Sun, Jeffrey Ecsedy, Jifeng Sun, Xue Li, Ping Wang
• Journal: Respiratory research (Respir Res) Vol. 20 Issue 1 Pg. 230 (Oct 23 2019) ISSN: 1465-993X [Electronic] England
• PMID: 31647033 (Publication Type: Journal Article)

Chemical References

• Azepines
• Biomarkers, Tumor
• MLN 8237
• Pyrimidines
• AURKA protein, human
• Aurora Kinase A

Topics

• Animals
• Aurora Kinase A (antagonists & inhibitors, metabolism)
• Azepines (pharmacology, therapeutic use)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, radiotherapy)
• Cell Line, Tumor
• Female
• Humans
• Lung Neoplasms (drug therapy, enzymology, radiotherapy)
• Mice
• Mice, Nude
• Pyrimidines (pharmacology, therapeutic use)
• Radiation Tolerance (drug effects, physiology)
• Retrospective Studies
• Xenograft Model Antitumor Assays (methods)