Abstract
BackgroundIn 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).MethodsHere, 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.ResultsWe 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.ConclusionsTaken 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.
Highlights
In mammalian cells, Aurora serine/threonine kinases (Aurora A, B, and C) are expressed in a cell cycledependent fashion as key mitotic regulators required for the maintenance of chromosomal stability
Aurora kinase A (AURKA) expression correlates with decreased survival in non-small cell lung cancer (NSCLC) Clinical characteristics of the 63 lung cancer patients, including age, sex, cancer type, stage, lymph node status, and the relationship between AURKA expression, are summarized in Additional file 1: Table S1
Progression-free survival (PFS) was only significantly different when using the Gehan-BreslowWilcoxon test, not the Log-rank (Mantel-Cox) test (p = 0.046 vs. p = 0.052, respectively), elevated expression of AURKA predicted an inferior time to progression (TTP) with a median duration of 12.3 vs. 19.6 months, respectively (p < 0.05, Fig. 1b, Table 1)
Summary
Aurora serine/threonine kinases (Aurora A, B, and C) are expressed in a cell cycledependent 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; whether its expression relates to patient survival and the association with radiotherapy remains unclear in non-small cell lung cancer (NSCLC). Overexpression of Aurora kinase is associated with tumorigenesis in multiple solid tumor types, including non-small cell lung cancer [13,14,15,16], and has been implicated in the development of resistance to chemotherapy [17, 18]. AURKA phosphorylates P53 at Ser-315 and reduces the transcriptional activity of P53 via regulation of P53 stability [23], while the phosphorylation of P53 at Ser-215 abrogates P53 DNA binding and transactivation activity. Normal P53 activity includes downregulating Fbxw, part of the ubiquitin ligase complex, which is responsible for targeting AURKA for destruction [25]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
