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

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

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

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

Aurora-B as an important kinase to adjust the cell normal mitosis is a potent target for cancer treatment. Aurora-B is overexpressed in a broad range of tumor and tumor cells are more sensitive while Aurora-B is inhibited. Due to the key role of the Aurora-B in cell mitosis, the development of its inhibitors is becoming more and more important. Several small molecules inhibit with a similar efficacy both Aurora-A and Aurora-B, however, in most cases the effects resemble Aurora-B disruption by genetic methods, indicating that Aurora-B represents an effective therapeutic target. There were several Aurora-B kinase inhibitors which had entered the clinics and displayed good antitumor activity. In this review, we will outline the functions of Aurora kinase B in normal cell division and in malignancy. We will focus on recent preclinical and clinical studies that have explored the mechanism of action and clinical effect of Aurora-B inhibitors in cancer treatment.
Animals ; Aurora Kinase B ; antagonists & inhibitors ; genetics ; metabolism ; Enzyme Activation ; Humans ; Mitosis ; Neoplasms ; drug therapy ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; RNA, Messenger ; metabolism

OBJECTIVETo study the expression of Aurora-B in non-small cell lung cancer (NSCLC) tissues and NSCLC cell lines.

METHODAurora-B expression was examined using immunohistochemical SP method in 91 stage I and 69 stage II-III NSCLC tissues and 40 adjacent tissues. The mRNA and protein expressions of Aurora-B in NSCLC cell lines (A549, H460 and H1299) were examined by RT-PCR and Western blotting, respectively.

RESULTSThe protein expression of Aurora-B was detected in 77.7% (94/121) of the tumor tissues and 9.8% (4/41) of the adjacent tissues, showing a significant difference between them (P<0.01). The positivity rate of Aurora-B protein was not related with the gender and age of NSCLC patients, but with lymph node metastasis, differentiation and histological type of NSCLC (P<0.05). Aurora-B was expressed in all the NSCLC cell lines (A549, H460 and H1299) at both mRNA and protein levels. A549 cells showed the highest expression of Aurora-B.

CONCLUSIONAurora-B protein is highly expressed in NSCLC tissues and cell lines, and may play a crucial role in the invasion, metastasis and development of NSCLC. The mRNA and protein expression levels of Aurora-B differ significantly between different NSCLC cell lines.

Adult ; Aged ; Aged, 80 and over ; Aurora Kinase B ; Aurora Kinases ; Carcinoma, Non-Small-Cell Lung ; metabolism ; pathology ; Female ; Humans ; Lung Neoplasms ; metabolism ; pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; Protein-Serine-Threonine Kinases ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Tumor Cells, Cultured

OBJECTIVETo study the expression of Aurora-B in human glioma tissue and its significance.

METHODSThe total RNA was extracted from 41 human glioma tissues and 11 normal brain tissues by Trizol reagent. After reverse transcription of the total RNA into cDNAs, Aurora-B mRNA expressions in these samples were detected by quantitative real-time PCR. The protein expression in these samples was detected using immunohistochemical staining.

RESULTSAurora-B mRNA and protein expressions were significantly increased in glioma tissues as compared with those in normal brain tissues.

CONCLUSIONAurora-B mRNA and protein show markedly higher expressions in glioma tissue, suggesting that Aurora-B may be one of the malignant biomarkers in the pathogenesis and progression of human glioma.

Aurora Kinase B ; Aurora Kinases ; Biomarkers, Tumor ; metabolism ; Brain Neoplasms ; enzymology ; pathology ; Female ; Glioma ; metabolism ; pathology ; Humans ; Male ; Protein-Serine-Threonine Kinases ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Tumor Cells, Cultured

OBJECTIVETo detect the gene expression profile in gastric cancer cell cycle and explain the mechanism of gastric cancer cell proliferation by a genomic study.

METHODSGastric cancer cells MKN45 were synchronized at G2/M and G1/S point by nocodazole-thymidine and double thymidine methods. The synchronizing degree of cells was monitored by flow cytometry. The gene expression profiles at G2/M point, M/G1 transition, G1 early phase, G1 late phase, G1/S point, S early phase, S late phase, G2 early phase and G2 late phase in MKN45 cell cycling were examined using cDNA microarray chips. Hierarchy analysis was conducted with a professional software package and the up-regulated genes at G1 late and G2 phase were analyzed according to gene database. Furthermore, the mRNA level of cyclin E, cyclin B, plk1 and STK15 in above mentioned nine points were measured by quatitative PCR.

RESULTS2001 genes were detected to be available at all 9 points via software processing, out of which 959 appeared up-regulated or down-regulated. 379 genes showed to be up-regulated at late G1 (147) or G2 phases (232), 40 at S and M phases (also up-regulated at G1 late and G2 phases). The 147 up-regulated genes at G1 late phase are involved in DNA metabolism, transcription and translation, protein transportation, ubiquitination and signal transduction, etc. The 232 up-regulated genes in G2 phase are involved in RNA synthesis and processing, intracellular protein transportation, cytoskeleton synthesis, signal transduction, apoptosis and anti-apoptosis, transcription regulation, ubiquitination, mitosis regulation and oncogene expression, etc. The mRNA level of 4 genes detected by quantitative PCR during cell cycle was in agreement with that detected by microarray.

CONCLUSIONDuring MKN45 cell cycling, the preparation for DNA synthesis and chromosome separation are conducted in G1 and G2, which are implicated in multiple genes, may be the main impetus of driving MKN45 cell cycle. Some of these genes may be related to tumor over-proliferation. The cDNA microarray technique has characteristic features such as reliability and can provide a great deal for future research on cell cycle related genes in gastric cancer.

Aurora Kinase A ; Aurora Kinases ; Cell Cycle ; genetics ; Cell Cycle Proteins ; genetics ; Cell Line, Tumor ; Cyclin B ; genetics ; Cyclin E ; genetics ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Oligonucleotide Array Sequence Analysis ; methods ; Polymerase Chain Reaction ; methods ; Protein-Serine-Threonine Kinases ; genetics ; Proto-Oncogene Proteins ; genetics ; RNA, Messenger ; genetics ; metabolism ; Stomach Neoplasms ; genetics ; pathology

OBJECTIVEThis case-control study was designed to detect the association between STK15 Phe31Ile polymorphism and colorectal cancer.

METHODSGenotypes were determined in 283 patients with colorectal cancer and 283 controls. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression model.

RESULTSThe frequency of the STK15 Ile/Ile genotype was significantly higher in cancer cases than in controls (50.2% vs. 36.8%; P = 0.02). Subjects with the Ile/Ile genotype had an increased risk for the occurrence of colorectal cancer compared with those with the STK15 Phe/Phe genotype (adjusted OR, 1.92; 95% CI, 1.13 - 3.27). No significant association was observed between this STK15 polymorphism and risk of metastasis of the cancer.

CONCLUSIONThese findings suggest that STK15 Phe/Ile polymorphism may be a genetic susceptibility factor for colorectal cancer among Chinese.

Adult ; Aged ; Amino Acid Substitution ; Aurora Kinase A ; Aurora Kinases ; Case-Control Studies ; Colonic Neoplasms ; enzymology ; genetics ; pathology ; Confidence Intervals ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Odds Ratio ; Polymorphism, Single Nucleotide ; Protein-Serine-Threonine Kinases ; genetics ; metabolism ; Rectal Neoplasms ; enzymology ; genetics ; pathology ; Risk Factors