OBJECTIVE: To investigate the fate and underlying mechanisms of G2 phase arrest in cancer cells elicited by ionizing radiation (IR). METHODS: Human melanoma A375 and 92-1 cells were treated with X-rays radiation or Aurora A inhibitor MLN8237 (MLN) and/or p21 depletion by small interfering RNA (siRNA). Cell cycle distribution was determined using flow cytometry and a fluorescent ubiquitin-based cell cycle indicator (FUCCI) system combined with histone H3 phosphorylation at Ser10 (pS10 H3) detection. Senescence was assessed using senescence-associated-β-galactosidase (SA-β-Gal), Ki67, and γH2AX staining. Protein expression levels were determined using western blotting. RESULTS: Tumor cells suffered severe DNA damage and underwent G2 arrest after IR treatment. The damaged cells did not successfully enter M phase nor were they stably blocked at G2 phase but underwent mitotic skipping and entered G1 phase as tetraploid cells, ultimately leading to senescence in G1. During this process, the p53/p21 pathway is hyperactivated. Accompanying p21 accumulation, Aurora A kinase levels declined sharply. MLN treatment confirmed that Aurora A kinase activity is essential for mitosis skipping and senescence induction. CONCLUSION Persistent p21 activation during IR-induced G2 phase blockade drives Aurora A kinase degradation, leading to senescence via mitotic skipping.
Humans ; Aurora Kinase A/metabolism* ; Cell Line, Tumor ; Mitosis ; Cell Cycle ; Radiation, Ionizing ; RNA, Small Interfering/metabolism* ; Cyclin-Dependent Kinase Inhibitor p21/metabolism*

BACKGROUND: Aurora kinases (AURKs) family plays a vital role not only in cell division but also in tumorigenesis. However, there are still rare systematic analyses of the diverse expression patterns and prognostic value of the AURKs family in breast cancer (BC). Systematic bioinformatics analysis was conducted to explore the biological role, prognostic value, and immunologic function of AURKs family in BC. METHODS: The expression, prognostic value, and clinical functions of AURKs family in BC were evaluated with several bioinformatics web portals: ONCOMINE Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter, cBioPortal, Metascape, GeneMANIA, and LinkedOmics; and the result was verified using human tissues. RESULTS: The expression of AURKA and AURKB were upregulated in BC in subgroup analyses based on tumor stage (all P   <  0.05). BC patients with high AURKA and AURKB expression had a worse overall survival, relapse-free survival, and distant metastasis-free survival (all P   <  0.05). Verification experiment revealed that AURKA and AURKB were upregulated in BC ( P  < 0.05). AURKA and AURKB were specifically associated with several tumor-associated kinases (polo-like kinase 1 and cyclin-dependent kinase 1), miRNAs (miR-507 and miR-381), and E2F transcription factor 1. Moreover, AURKA and AURKB were correlated with immune cell infiltration. Functional enrichment analysis revealed that AURKA and AURKB were involved in the cell cycle signaling pathway, platinum drug resistance signaling pathway, ErbB signaling pathway, Hippo signaling pathway, and nucleotide-binding and oligomerization domain-like receptor signaling pathway. CONCLUSIONS Aurora kinases AURKA and AURKB could be employed as novel prognostic biomarkers or promising therapeutic targets for BC.
Humans ; Female ; Aurora Kinase A/metabolism* ; Aurora Kinase B/metabolism* ; Prognosis ; Breast Neoplasms/genetics* ; Neoplasm Recurrence, Local ; MicroRNAs

Aurora kinase A (AURKA),a family member of aurora kinases,is involved in mitotic entry,maturation and separation of centrosome,assembly and stabilization of bipolar spindle,and condensation and separation of chromosome.Studies have demonstrated that AURKA plays a similar role in meiosis,while the specific mechanism and the similarities and differences in its role between meiosis and mitosis remain unclear.Therefore,we reviewed the studies about the localization and activation of AURKA in oocyte meiosis,and compared the role of AURKA in regulating spindle formation,activating spindle assembly checkpoint,and correcting the kinetochore-microtubule attachment between the meiosis of oocytes and the mitosis of somatic cells.This review will lay a theoretical foundation for revealing the mechanism of AURKA in the regulation of cell division and for the clinical research related to cancer and reproduction.
Aurora Kinase A/genetics* ; Cell Cycle Proteins/genetics* ; Chromosome Segregation ; Humans ; Meiosis ; Oocytes

Aurora kinase A plays an essential role in mitosis including chromosome separation and cytokinesis. Aberrant expression and activity of Aurora kinase A is associated with numerous malignancies including colorectal cancer followed by poor prognosis. The aim of this study is to determine the inhibitory effects of LDD970, an indirubin derivative, on Aurora kinase A in HT29 colorectal cancer cells. In vitro kinase assay revealed that, LDD970 inhibited levels of activated Aurora kinase A (IC₅₀=0.37 mM). The inhibitory effects of LDD970 on Aurora kinase A, autophosphorylation and phosphorylation of histone H3 (Ser10), were confirmed by immunoblot analysis. Moreover, LDD970 inhibited migration of HT29 cells and upregulated apoptosis-related protein cleaved PARP. In cell viability assay, LDD970 was observed to suppress HT29 cell growth (GI₅₀=4.22 µM). Although further studies are required, results of the present study suggest that LDD970 provide a valuable insight into small molecule indirubin derivative for therapeutic potential in human colorectal cancer.
Aurora Kinase A* ; Cell Survival ; Colorectal Neoplasms* ; Cytokinesis ; Histones ; HT29 Cells ; Humans* ; In Vitro Techniques ; Mitosis ; Phosphorylation ; Phosphotransferases ; Prognosis

BACKGROUND: Aurora kinase A (AURKA), or STK15/BTAK, is a member of the serine/threonine kinase family and plays important roles in mitosis and chromosome stability. This study investigated the clinical significance of AURKA expression in colorectal cancer patients in Korea. METHODS: AURKA protein expression was evaluated by immunohistochemistry in 151 patients with colorectal adenocarcinoma using tissue microarray blocks. We analyzed the relationship between clinicopathological characteristics and AURKA expression. In addition, the prognostic significance of various clinicopathological data for progression-free survival (PFS) was assessed. Also we evaluated copy number variations by array comparative genomic hybridization and AURKA gene amplification using fluorescence in situ hybridization in colorectal carcinoma tissues. RESULTS: AURKA gene amplification was found more frequently in the 20q13.2–13.33 gain-positive group than the group with no significant gain on the AURKA-containing locus. AURKA protein expression was detected in 45% of the cases (68/151). Positive staining for AURKA was observed more often in male patients (p = .035) and distally located tumors (p = .021). PFS was shorter in patients with AURKA expression compared to those with low-level AURKA expression (p < .001). Univariate analysis revealed that AURKA expression (p = .001), age (p = .034), lymphatic invasion (p = .001), perineural invasion (p = .002), and TNM stage (p = .013) significantly affected PFS. In a multivariate analysis of PFS, a Cox proportional hazard model confirmed that AURKA expression was an independent and significant prognostic factor in colorectal adenocarcinoma (hazard ratio, 3.944; p < .001). CONCLUSIONS: AURKA could serve as an independent factor to predict a poor prognosis in Korean colorectal adenocarcinoma patients.
Adenocarcinoma* ; Aurora Kinase A* ; Chromosomal Instability ; Colorectal Neoplasms ; Comparative Genomic Hybridization ; Disease-Free Survival ; Fluorescence ; Gene Amplification ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Korea ; Male ; Mitosis ; Multivariate Analysis ; Phosphotransferases ; Prognosis ; Proportional Hazards Models

Coordination of cell division and cell fate is crucial for the successful development of mammalian early embryos. Aurora kinases are evolutionarily conserved serine/threonine kinases and key regulators of mitosis. Aurora kinase B (AurkB) is ubiquitously expressed while Aurora kinase C (AurkC) is specifically expressed in gametes and preimplantation embryos. We found that increasing AurkC level in one blastomere of the 2-cell embryo accelerated cell division and decreasing AurkC level slowed down mitosis. Changing AurkB level had the opposite effect. The kinase domains of AurkB and AurkC were responsible for their different ability to phosphorylate Histone H3 Serine 10 (H3S10P) and regulate metaphase timing. Using an Oct4-photoactivatable GFP fusion protein (Oct4-paGFP) and fluorescence decay after photoactivation assay, we found that AurkB overexpression reduced Oct4 retention in the nucleus. Finally, we show that blastomeres with higher AurkC level elevated pluripotency gene expression, which were inclined to enter the inner cell mass lineage and subsequently contributed to the embryo proper. Collectively, our results are the first demonstration that the activity of mitotic kinases can influence cell fate decisions in mammalian preimplantation embryos and have important implications to assisted reproduction.
Animals ; Aurora Kinase B ; metabolism ; Aurora Kinase C ; metabolism ; Blastocyst ; metabolism ; Gene Expression Regulation, Developmental ; physiology ; Histones ; metabolism ; Mice ; Phosphorylation ; physiology

Approximately 2,300 genes are found to be associated with spermiogenesis and their expressions play important roles in the regulation of spermiogenesis. In recent years, more and more attention has been focused on the studies of the genes associated with oligospermia, asthenospermia and teratospermia and their molecular mechanisms. Some genes, such as GSTM1, DNMT3L, and CYP1A1, have been shown to be potentially associated with oligospermia; some, such as CATSPER1, CRISP2, SEPT4, TCTE3, TEKT4, and DNAH1, with asthenospermia; and still others, such as DPY19L2 and AURKC, with teratospermia. These findings have provided a molecular basis for the studies of the pathogenesis of oligospermia, asthenospermia and teratospermia, as well as a new approach to the exploration of new diagnostic and therapeutic techniques.
Asthenozoospermia ; genetics ; Aurora Kinase C ; genetics ; Calcium Channels ; genetics ; Cytochrome P-450 CYP1A1 ; genetics ; Cytoplasmic Dyneins ; DNA (Cytosine-5-)-Methyltransferases ; genetics ; Dyneins ; genetics ; Glutathione Transferase ; genetics ; Glycoproteins ; genetics ; Humans ; Male ; Membrane Proteins ; genetics ; Microtubule Proteins ; genetics ; Oligospermia ; genetics ; Spermatogenesis ; genetics ; Teratozoospermia ; genetics

Objective: To investigate the association of a very common mutation of c.144delC in the aurora kinase C (AURKC) gene with idiopathic teratozoospermia in Chinese infertile men in Sichuan. METHODS: Using polymerase chain reaction (PCR) and next-generation sequencing, we analyzed the correlation between c.144delC polymorphism of the AURKC gene and male infertility in 98 idiopathic teratozoospermia patients in comparison with 162 normal fertile men. RESULTS: Neither c.144delC mutation nor other meaningful mutations were detected in the AURKC gene in the 98 idiopathic teratozoospermia patients or the 162 normal controls. CONCLUSIONS Teratozoospermia is not correlated with c.144delC mutation in the AURKC gene in the men of the Sichuan area. Therefore, large-scale genotyping of the AURKC gene may not be necessary clinically among Chinese patients with idiopathic teratozoospermia.
Aurora Kinase C ; genetics ; Humans ; Male ; Mutation ; genetics ; Polymorphism, Genetic ; Spermatozoa ; Teratozoospermia ; genetics

The aim of this study is to evaluate anti-tumor activities and mechanism of a novel kinase inhibitor ZLJ213 which targeted Aurora A and vascular endothelial growth factor receptor (VEGFR) in vitro and in vivo against human colon cancer. Results showed that ZLJ213 inhibited cell proliferation and induced cell cycle arrest and apoptosis of HCT1 16 and SW48 cell lines. In HCT116-derived xenograft, ZLJ213 dosed at 100 mg · kg(-1) inhibited tumor growth by 73.24%. The IC50 of ZLJ213 on the expression of p-Aurora A was 0.258 µmol · L(-1) analyzed by ELISA. Under the concentration of 0.08 µmol · L(-1), ZLJ213 could inhibit the activities of Aurora A, Histone H3 and VEGFR of HCT116 and SW48 cell lines. Simultaneously, ZLJ213 induced activation of Caspase 3 and PARP cleavage. Above data suggested that ZLJ213 had the ability to inhibit cell proliferation and induce cell apoptosis both in vitro and in vivo in colon cancer, and down-regulate the expression of p-Aurora A and p-VEGFR. ZLJ213 might be a potential therapeutic agent against colon cancer.
Animals ; Apoptosis ; Aurora Kinase A ; antagonists & inhibitors ; Cell Cycle Checkpoints ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; Colonic Neoplasms ; pathology ; Humans ; Protein Kinase Inhibitors ; pharmacology ; Receptors, Vascular Endothelial Growth Factor ; metabolism ; Xenograft Model Antitumor Assays

OBJECTIVEThe aim of this study was to investigate the prognostic value of combined expression of Aurora A, Ki-67, p53 and p21 WAF1 in patients after curative resection of non-small cell lung cancer (NSCLC).

METHODSExpressions of Aurora A, Ki-67, p53 and p21 WAF1 in 58 tumor samples from resected primary NSCLCs were detected by immunohistochemistry. The correlation of proteins, survival and clinicopathological characteristics was analyzed.

RESULTSThe positive rates of Aurora A, Ki-67, p53 and p21 WAF1 expression were 89.7% (52/58), 53.4% (31/58), 46.6% (27/58) and 34.5% (20/58), respectively. Aurora A expression was positively correlated with nodal metastasis (69.2% vs. 37.8%, P = 0.045). The univariable analysis showed that the overall survival (OS) was 75.0%in patients with low Aurora A expression and 46.0% in patients with high Aurora A expression (P = 0.039). The 3-year survival rate was 40.0% in patients with positive expression of Aurora A and p53, 65.0% in the patients with positive expression of Aurora A or p53, and 82.1% in the patients with negative expression of Aurora A and p53 (P = 0.039). The Cox regression model showed that combined expression of Aurora and p53 is an independent factor affecting the prognosis of NSCLC patients (P = 0.015).

CONCLUSIONSOur findings suggest that the positive expression of Aurora A, Ki-67 and p53 proteins is an unfavorable factor affecting the prognosis for NSCLC patients, and the overexpression of Aurora A is an independent unfavorable factor association with shorter OS in NSCLC patients. Detection of positive Aurora A and p53 expression may be a useful predictive prognostic indicator for NSCLC patients.

Aurora Kinase A ; metabolism ; Carcinoma, Non-Small-Cell Lung ; metabolism ; mortality ; surgery ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; Humans ; Immunohistochemistry ; Ki-67 Antigen ; metabolism ; Lung Neoplasms ; metabolism ; mortality ; surgery ; Prognosis ; Survival Analysis ; Survival Rate ; Tumor Suppressor Protein p53 ; metabolism