Role of AURKB Inhibition in Reducing Proliferation and Enhancing Effects of Radiotherapy in Triple-Negative Breast Cancer.

Breast cancer is a leading cause of cancer-related deaths in females. Triple-negative breast cancer (TNBC) subtype is the most aggressive form of breast cancer that lacks biomarkers and effective targeted therapies. Its high degree of heterogeneity as well as innate and acquired resistance to treatment creates further barriers in achieving positive clinical outcomes in TNBC. Thus, development of novel treatment approaches in TNBC is of high clinical significance. Multimodality approaches with targeted agents and radiotherapy (RT) are promising for increasing efficacy of treatment and circumventing resistance. Here we examined anticancer effects of the Aurora Kinase B (AURKB) inhibitor AZD1152 as a single agent and in combination with RT using various TNBC cell lines, MDA-MB-468, MDA-MB-231 and SUM-159. We observed that AZD1152 alone effectively inhibited colony formation in TNBC cell lines. The combination of AZD1152 at IC50 concentrations together with ionizing radiation further reduced colony formation as compared to the single agent treatment. Our data support the notion that inhibition of the AURKB pathway is a promising strategy for treatment and radiosensitization of TNBC and warrants further translational studies.

Breast cancer is a leading cause of cancer death in women globally. The triple negative breast cancer subtype confers the poorest oncologic outcomes and requires novel treatment approaches. Development of new therapeutics as well as combination treatments with radiation are crucial. Aurora Kinase B (AURKB) protein regulates cell division that is often altered in breast cancer, contributing to tumor pathogenesis. This study examined the combination of an AURKB inhibitor, AZD1152, with radiation therapy, compared to single-agent treatments, in treating triple negative breast cancer cells. Our results show that AZD1152 and ionizing radiation alone were able to delay cancer cell proliferation effectively. However, their combination further significantly inhibited cell proliferation compared to single-agent treatments. This suggests that further studies on this combination would be valuable in developing novel treatment strategies for breast cancer.

Investigating the chemo-preventive role of noscapine in lung carcinoma via therapeutic targeting of human aurora kinase B.

Lung carcinoma is the major contributor to global cancer incidence and one of the leading causes of cancer-related mortality worldwide. Irregularities in signal transduction events, genetic alterations, and mutated regulatory genes trigger cancer development and progression. Selective targeting of molecular modulators has substantially revolutionized cancer treatment strategies with improvised efficacy. The aurora kinase B (AURKB) is a critical component of the chromosomal passenger complex and is primarily involved in lung cancer pathogenesis. Since AURKB is an important therapeutic target, the design and development of its potential inhibitors are attractive strategies. In this study, noscapine was selected and validated as a possible inhibitor of AURKB using integrated computational, spectroscopic, and cell-based assays. Molecular docking analysis showed noscapine occupies the substrate-binding pocket of AURKB with strong binding affinity. Subsequently, MD simulation studies confirmed the formation of a stable AURKB-noscapine complex with non-significant alteration in various trajectories, including RMSD, RMSF, Rg, and SASA. These findings were further experimentally validated through fluorescence binding studies. In addition, dose-dependent noscapine treatment significantly attenuated recombinant AURKB activity with an IC50 value of 26.6 µM. Cell viability studies conducted on A549 cells and HEK293 cells revealed significant cytotoxic features of noscapine on A549 cells. Furthermore, Annexin-PI staining validated that noscapine triggered apoptosis in lung cancer cells, possibly via an intrinsic pathway. Our findings indicate that noscapine-based AURKB inhibition can be implicated as a potential therapeutic strategy in lung cancer treatment and can also provide a novel scaffold for developing next-generation AURKB-specific inhibitors.

Synthesis and antitumor activities of novel 3-(6-aminopyridin-3-yl)benzamide derivatives: Inducing cell cycle arrest and apoptosis via AURKB transcription inhibition.

Here, a series of 3-(6-aminopyridin-3-yl) benzamide derivatives were designed and synthesized. Cell viability assay indicated that most compounds exhibited potent antiproliferative activity against all the tested cancer cells. Among them, compound 7l displayed the best antiproliferative activity particularly in A549 cells, with an IC50 value of 0.04 ± 0.01 µM. RNA-seq analysis was employed to explore the potential pathways related to the antiproliferative activity of compound 7l. The data revealed that 7l exerted antiproliferative activity mainly by regulating cell cycle, DNA replication and p53 signaling pathway. Indeed, compound 7l induced G2/M phase arrest by AURKB transcription inhibition and resulted in cell apoptosis via p53 signaling pathway. Most importantly, compound 7l demonstrated potent antitumor activity in A549 xenograft tumor model. Collectively, 7l might be a promising lead compound for the development of new therapeutic agents for AURKB overexpressed or mutated cancers.

Exploring the anticancer potential of fluoro flavone analogues: insights from molecular docking and dynamics studies with Aurora Kinase B.

Aurora Kinase B belongs to the serine kinase family. It plays an essential role in cell division and participates in mitosis and chromatid segregation. Overexpression, polymorphism, and splicing variants in the protein lead to tumorigenesis, leading to cancer. Flavones belong to the class of flavonoids and are derived from plants and show anti-cancer activities. Fluoro flavones and their analogs are taken from the PubChem database, resulting in 3882 compounds which is 90% similar to the fluoro flavones. Lipinski's rule of five, REOS and PAINS drug-like filters were applied which resulted 2448 compounds. These compounds are docked with Aurora Kinase B using SP and XP modules of Glide software. The best binding scores for SP docking were - 9.153 kcal/mol for the compound with CID: 44298667, and XP docking was - 10.287 kcal/mol with CID: 101664315. Enrichment calculations were done using Aurora Kinase B's decoys to validate the docking result. The resulting R2 = 0.96 from enrichment calculations suggests that the docking protocol is valid. The SP and XP docking lead compounds and the Fluoro flavone were subjected to 100 ns MD simulation to probe the protein-ligand complex stability. Also, the binding free energies between the Aurora kinase B and lead compounds were computed by Prime MM/GBSA module. The result suggests that the lead compounds bind more strongly with Aurora Kinase B than the Fluoro flavone. These lead compounds can be further evaluated in vitro and in vivo and can be used as future novel drugs for the curation of cancer.

AURKB promotes bladder cancer progression by deregulating the p53 DNA damage response pathway via MAD2L2.

BACKGROUND: Bladder cancer (BC) is the most common urinary tract malignancy. Aurora kinase B (AURKB), a component of the chromosomal passenger protein complex, affects chromosomal segregation during cell division. Mitotic arrest-deficient 2-like protein 2 (MAD2L2) interacts with various proteins and contributes to genomic integrity. Both AURKB and MAD2L2 are overexpressed in various human cancers and have synergistic oncogenic effects; therefore, they are regarded as emerging therapeutic targets for cancer. However, the relationship between these factors and the mechanisms underlying their oncogenic activity in BC remains largely unknown. The present study aimed to explore the interactions between AURKB and MAD2L2 and how they affect BC progression via the DNA damage response (DDR) pathway. METHODS: Bioinformatics was used to analyze the expression, prognostic value, and pro-tumoral function of AURKB in patients with BC. CCK-8 assay, colony-forming assay, flow cytometry, SA-ß-gal staining, wound healing assay, and transwell chamber experiments were performed to test the viability, cell cycle progression, senescence, and migration and invasion abilities of BC cells in vitro. A nude mouse xenograft assay was performed to test the tumorigenesis ability of BC cells in vivo. The expression and interaction of proteins and the occurrence of the senescence-associated secretory phenotype were detected using western blot analysis, co-immunoprecipitation assay, and RT-qPCR. RESULTS: AURKB was highly expressed and associated with prognosis in patients with BC. AURKB expression was positively correlated with MAD2L2 expression. We confirmed that AURKB interacts with, and modulates the expression of, MAD2L2 in BC cells. AURKB knockdown suppressed the proliferation, migration, and invasion abilities of, and cell cycle progression in, BC cells, inducing senescence in these cells. The effects of AURKB knockdown were rescued by MAD2L2 overexpression in vitro and in vivo. The effects of MAD2L2 knockdown were similar to those of AURKB knockdown. Furthermore, p53 ablation rescued the MAD2L2 knockdown-induced suppression of BC cell proliferation and cell cycle arrest and senescence in BC cells. CONCLUSIONS: AURKB activates MAD2L2 expression to downregulate the p53 DDR pathway, thereby promoting BC progression. Thus, AURKB may serve as a potential molecular marker and a novel anticancer therapeutic target for BC.

Overexpression of Aurora Kinase B Is Correlated with Diagnosis and Poor Prognosis in Hepatocellular Carcinoma.

Aurora kinase B (AURKB) overexpression promotes tumor initiation and development by participating in the cell cycle. In this study, we focused on the mechanism of AURKB in hepatocellular carcinoma (HCC) progression and on AURKB's value as a diagnostic and prognostic biomarker in HCC. We used data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) to analyze AURKB expression in HCC. We found that the expression levels of AURKB in HCC samples were higher than those in the corresponding control group. R packages were used to analyze RNA sequencing data to identify AURKB-related differentially expressed genes (DEGs), and these genes were found to be significantly enriched during the cell cycle. The biological function of AURKB was verified, and the results showed that cell proliferation was slowed down and cells were arrested in the G2/M phase when AURKB was knocked down. AURKB overexpression resulted in significant differences in clinical symptoms, such as the clinical T stage and pathological stage. Kaplan-Meier survival analysis, Cox regression analysis, and Receiver Operating Characteristic (ROC) curve analysis suggested that AURKB overexpression has good diagnostic and prognostic potential in HCC. Therefore, AURKB may be used as a potential target for the diagnosis and cure of HCC.

Influence of different pH milieu on the structure and function of human Aurora kinase B protein (AURK-B): Amalgamation of both spectroscopic and computational approach.

Aurora kinase B (AURK-B) is a serine/threonine kinase protein that plays an essential role in chromosomal separation during the cell cycle event. AURK-B is highly expressed in various types of cancer such as human seminoma, thyroid carcinoma, non-small cell lung carcinoma (NSCLC), oral carcinoma, and gastric cancer. Hence, it is a potential therapeutic target in the treatment of various cancers. The structure of AURK-B in complex with one of its substrate inner centromeric protein (INCENP) is present, but the structural and functional characterization of native AURK-B at different pH environment is still unexplored.This study determines the effect of different pH milieu on the structure and function of AURK-B protein wherein the influence of pH on the protein conformation was probed using Circular dichroism (CD) and fluorescence spectroscopy. The structural studies were further combined with functional activity assay to observe the change in kinase activity at various pH milieu (2.0-11.0). CD and fluorescence spectroscopy experiments dictate that at high acidic conditions (pH 2.0 - 5.0), the secondary and tertiary structures of AURK-B become distorted, leading to diminished activity. The protein, however, was observed to stabilize towards pH 7.0 - 8.0 with minimal structure alteration over the basic pH range (pH 9.0 -11.0). The measured spectroscopic structural features were found to be in-line with obtained experimental kinase activity assays. Further, in-vitro experiments indicate that the enzyme is maximally active at pH 8.0. More ordered conformation and compact structure was observed at this pH (pH 8.0) as compared to other pH values through molecular dynamics simulation studies (MDS). As AURK-B localizes itself in the intracellular compartment, this study may provide a clue about the role of different pH environments in enhancing cancer growth, proliferation, and invasion.

Probing Baicalin as potential inhibitor of Aurora kinase B: A step towards lung cancer therapy.

Cell cycle regulators play pivotal roles as their dysregulation, leads to atypical proliferation and intrinsic genomic instability in cancer cells. Abnormal expression and functioning of Aurora kinase B (AURKB) are associated with cancer pathogenesis and thus exploited as a potential therapeutic target for the development of anti-cancer therapeutics. To identify effective AURKB inhibitors, a series of polyphenols was investigated to check their potential to inhibit recombinant AURKB. Their binding affinities were experimentally validated through fluorescence binding studies. Enzyme inhibition assay revealed that Mangiferin and Baicalin significantly inhibited AURKB activity with an IC50 values of 20.0 µM and 31.1 µM, respectively. To get atomistic insights into the binding mechanism, molecular docking and MD simulations of 100 ns were performed. Both compounds formed many non-covalent interactions with the residues of the active site pocket of AURKB. In addition, minimal conformational changes in the structure and formation of stable AURKB-ligand complex were observed during MD simulation analysis. Finally, cell-based studies suggested that Baicalin exhibited in-vitro cytotoxicity and anti-proliferative effects on lung cancer cell lines. Conclusively, Baicalin may be considered a promising therapeutic molecule against AURKB, adding an additional novel lead to the anti-cancer repertoire.

Interaction between Human Papillomavirus-Encoded E6 Protein and AurB Induces Cell Immortalization and Proliferation-A Potential Target of Intervention.

The human papillomavirus E6 and E7 oncoproteins interact with a different subset of host proteins, leading to dysregulation of the apoptotic, cell cycle, and signaling pathways. In this study, we identified, for the first time, that Aurora kinase B (AurB) is a bona fide interacting partner of E6. We systematically characterized the AurB-E6 complex formation and its consequences in carcinogenesis using a series of in vitro and cell-based assays. We also assessed the efficacy of Aurora kinase inhibitors in halting HPV-mediated carcinogenesis using in vitro and in vivo models. We showed that AurB activity was elevated in HPV-positive cells, and this correlated positively with the E6 protein level. E6 interacted directly with AurB in the nucleus or mitotic cells. A previously unidentified region of E6, located upstream of C-terminal E6-PBM, was important for AurB-E6 complex formation. AurB-E6 complex led to reduced AurB kinase activity. However, the AurB-E6 complex increased the hTERT protein level and its telomerase activity. On the other hand, AurB inhibition led to the inhibition of telomerase activity, cell proliferation, and tumor formation, even though this may occur in an HPV-independent manner. In summary, this study dissected the molecular mechanism of how E6 recruits AurB to induce cell immortalization and proliferation, leading to the eventual cancer development. Our findings revealed that the treatment of AZD1152 exerted a non-specific anti-tumor effect. Hence, a continuous effort to seek a specific and selective inhibitor that can halt HPV-mediated carcinogenesis should be warranted.

Hepatitis C virus fitness can influence the extent of infection-mediated epigenetic modifications in the host cells.

Introduction: Cellular epigenetic modifications occur in the course of viral infections. We previously documented that hepatitis C virus (HCV) infection of human hepatoma Huh-7.5 cells results in a core protein-mediated decrease of Aurora kinase B (AURKB) activity and phosphorylation of Serine 10 in histone H3 (H3Ser10ph) levels, with an affectation of inflammatory pathways. The possible role of HCV fitness in infection-derived cellular epigenetic modifications is not known. Methods: Here we approach this question using HCV populations that display a 2.3-fold increase in general fitness (infectious progeny production), and up to 45-fold increase of the exponential phase of intracellular viral growth rate, relative to the parental HCV population. Results: We show that infection resulted in a HCV fitness-dependent, average decrease of the levels of H3Ser10ph, AURKB, and histone H4 tri-methylated at Lysine 20 (H4K20m3) in the infected cell population. Remarkably, the decrease of H4K20m3, which is a hallmark of cellular transformation, was significant upon infection with high fitness HCV but not upon infection with basal fitness virus. Discussion: Here we propose two mechanisms ─which are not mutually exclusive─ to explain the effect of high viral fitness: an early advance in the number of infected cells, or larger number of replicating RNA molecules per cell. The implications of introducing HCV fitness as an influence in virus-host interactions, and for the course of liver disease, are warranted. Emphasis is made in the possibility that HCV-mediated hepatocellular carcinoma may be favoured by prolonged HCV infection of a human liver, a situation in which viral fitness is likely to increase.

Pharmacophore Synergism in Diverse Scaffold Clinches in Aurora Kinase B.

Aurora kinase B (AKB) is a crucial signaling kinase with an important role in cell division. Therefore, inhibition of AKB is an attractive approach to the treatment of cancer. In the present work, extensive quantitative structure-activity relationships (QSAR) analysis has been performed using a set of 561 structurally diverse aurora kinase B inhibitors. The Organization for Economic Cooperation and Development (OECD) guidelines were used to develop a QSAR model that has high statistical performance (R2tr = 0.815, Q2LMO = 0.808, R2ex = 0.814, CCCex = 0.899). The seven-variable-based newly developed QSAR model has an excellent balance of external predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The QSAR analysis successfully identifies not only the visible pharmacophoric features but also the hidden features. The analysis indicates that the lipophilic and polar groups-especially the H-bond capable groups-must be present at a specific distance from each other. Moreover, the ring nitrogen and ring carbon atoms play important roles in determining the inhibitory activity for AKB. The analysis effectively captures reported as well as unreported pharmacophoric features. The results of the present analysis are also supported by the reported crystal structures of inhibitors bound to AKB.

High expression of aurora kinase B predicts poor prognosis in hepatocellular carcinoma after curative surgery and its effects on the tumor microenvironment.

Background: Currently, the only broadly used biomarker for hepatocellular carcinoma (HCC), alpha fetoprotein (AFP), has multiple limitations and the need for novel biomarkers is urgent. Aurora kinase B (AURKB) is a key mitotic protein kinase which performs a critical function in cell cycle progression. Nonetheless, neither the function nor the mechanism of AURKB in HCC following curative surgery is fully grasped at this time. This study sought to evaluate the impact of AURKB on prognosis and the tumor immune microenvironment (TIME) in HCC. Methods: We evaluated both the expression profile of AURKB in HCC and its clinical value using online databases and clinical specimens. The prognostic value of AURKB was studied by Kaplan-Meier survival analysis, and the link between AURKB and tumor-infiltrating immune cells (TIICs) were analyzed. Results: We found the mRNA expression patterns of AURKB were remarkably upregulated in HCC in contrast with adjoining normal tissues (P<0.001). Upregulation of the AURKB protein in HCC was additionally verified by clinical samples. The expression of AURKB was substantially associated with Child-Pugh, microvascular invasion (MVI), Edmondson-Steiner grade, and tumor recurrence. Furthermore, patients diagnosed with HCC who had a low AURKB expression had a better. Our data suggested age [hazard ratio (HR): 1.34], alanine aminotransferase (ALT) (HR: 1.65), tumor size (HR: 1.99), mor number (HR: 1.60), MVI (HR: 1.93), grade (HR: 5.58), and AURKB expression (HR: 3.63) independently functioned as prognostic risk indicators for HCC (P<0.05). Importantly, we also found AURKB expression was inversely linked to resting natural killer (NK) cells, M2 macrophages, activated mast cells, and naive B cells, and positively linked to M0 macrophages, T follicular helper cells (Tfh), regulatory T cells (Treg), and resting myeloid dendritic cells. In addition, AURKB expression was also positively linked to the immune checkpoints of PDCD1, CD274, CTLA4, and LAG3. Finally, 1,696 DEGs were discovered, and were predominantly implicated in chromosome segregation, cell cycle, xenobiotic metabolic process, calcium signaling pathway, bile secretion, tyrosine metabolism, and DNA replication. Conclusions: AURKB may be a potential prognostic biomarker for HCC after curative surgery, which correlates with MVI and the TIME in HCC.

The Effect of Circumscribed Exposure to the Pan-Aurora Kinase Inhibitor VX-680 on Proliferating Euploid Cells.

Small molecule inhibitors of aurora kinases are currently being investigated in oncology clinical trials. The long-term effects of these inhibitors on proliferating euploid cells have not been adequately studied. We examined the effect of the reversible pan-aurora kinase inhibitor VX-680 on p53-competent human euploid cells. Circumscribed treatment with VX-680 blocked cytokinesis and arrested cells in G1 or a G1-like status. Approximately 70% of proliferatively arrested cells had 4N DNA content and abnormal nuclei. The remaining 30% of cells possessed 2N DNA content and normal nuclei. The proliferative arrest was not due to the activation of the tumor suppressor Rb and was instead associated with rapid induction of the p53-p21 pathway and p16. The induction was particularly evident in cells with nuclear abnormalities but was independent of activation of the DNA damage response. All of these effects were correlated with the potent inhibition of aurora kinase B. After release from VX-680, the cells with normal nuclei robustly resumed proliferation whereas the cells with abnormal nuclei underwent senescence. Irrespective of their nuclear morphology or DNA content, cells pre-treated with VX-680 failed to grow in soft agar or form tumors in mice. Our findings indicate that an intermittent treatment strategy might minimize the on-target side effects of Aurora Kinase B (AURKB) inhibitory therapies. The strategy allows a significant fraction of dividing normal cells to resume proliferation.

Non-SMC condensin I complex subunit H promotes the malignant progression and cisplatin resistance of breast cancer MCF-7 cells.

Breast cancer is one of the most frequently diagnosed types of cancer worldwide. The present study aimed to investigate the role and underlying regulatory mechanism of non-structural maintenance of chromosome condensin I complex subunit H (NCAPH) in the malignant progression and cisplatin (DDP) resistance of breast cancer cells. Therefore, the mRNA and protein expression levels of NCAPH were first determined in breast cancer cells via reverse transcription-quantitative PCR and western blotting. Furthermore, following transfection of NCAPH interference plasmids, the effect of NCAPH knockdown on cell proliferation, migration, invasion were also assessed using CCK-8, wound healing and Transwell assays. Apoptosis was evaluated using TUNEL assay, and western blotting was performed in breast cancer cells and DDP-resistant breast cancer cells. The association between NCAPH and its downstream target, aurora kinase B (AURKB), was verified using bioinformatic analysis and the co-immunoprecipitation assay. Furthermore, the effect of AURKB overexpression on the aforementioned processes and the Akt/mTOR signaling pathway were also assessed. The results demonstrated that NCAPH mRNA and protein expression levels were significantly upregulated in breast cancer cells, whereas NCAPH knockdown significantly attenuated the proliferation, migration and invasion of breast cancer cells. NCAPH silencing also exacerbated the apoptosis of DDP-resistant breast cancer cells. AURKB mRNA and protein expression levels were also significantly upregulated in MCF-7 cells, whereas its overexpression significantly reversed the effects of NCAPH knockdown on breast cancer cells and the Akt/mTOR signaling pathway. Overall, NCAPH knockdown significantly downregulated AURKB mRNA and protein expression levels to block the Akt/mTOR signaling pathway and inhibited breast cancer cell proliferation, migration, invasion, and aggravate DDP-resistant breast cancer cell apoptosis, indicating that NCAPH may serve as a promising therapeutic target for breast cancer.

Clinical outcomes associated with expression of aurora kinase and p53 family members in muscle-invasive bladder cancer.

Biomarkers are needed in muscle-invasive bladder cancer (MIBC). We previously reported that high tumor aurora kinase (AURK) A expression identifies patients with MIBC with poor prognosis. Aberrant p53 expression has also been associated with poor outcomes in MIBC, though to the best of our knowledge, co-expression rates of p53 and aurora kinases have not been previously described in MIBC. As aurora kinase and p53 family members may co-regulate each other, the present study investigated whether tumor p53 or p63 protein expression influenced the prognostic value of AURKA in a pilot study of 50 patients with MIBC treated with curative intent. Immunohistochemistry for AURKA, AURKB, p53 and p63 were performed on archival pre-treatment tumor specimens and correlated with clinical outcomes in patients with MIBC who received neoadjuvant chemotherapy (NAC) prior to cystectomy. Baseline p53 [hazard ratio (HR) 1.46; 95% confidence interval (CI)=0.55-3.9; P=0.448) and p63 (HR 2.02; 95% CI=0.51-8.1; P=0.313) protein expression did not predict for overall survival (OS). Low p53 protein expression did not correlate with high AURKA (φ=0.190) or AURKB (φ=0.075) expression. However, in tumors with low p53 expression (n=17), the presence of either high AURKA or AURKB expression levels predicted an increased risk for relapse (HR 27.1; 95% CI=2.7-270.1; P=0.005) and mortality (HR 14.9; 95% CI=2.3-95.6; P=0.004) compared to tumors with both low AURKA and AURKB levels. The relationship between p63 and AURKA/B expression levels was not tested due to the prevalence (80%) of high p63 expression in the present cohort. In tumors with low AURKA expression, p53 status did not predict for OS (HR 0.62; 95% CI 0.2-3.2; P=0.572). In multivariable analysis, only high baseline AURKA expression predicted for inferior OS (HR 4.9; 95% CI 1.7-14.1; P=0.003). To the best of our knowledge, the present study was the first to report co-expression of p53 and aurora kinase family members in MIBC, and although wild-type p53 may regulate the aurora kinases in preclinical models, the adverse prognostic value of tumor AURKA overexpression was independent from baseline tumor p53 protein expression in the present cohort. AURKA remains an important prognostic biomarker in patients with MIBC and warrants further evaluation in prospective studies to validate whether baseline AURKA can identify patients that are unlikely to benefit from standard of care with NAC.

A dual aurora and lim kinase inhibitor reduces glioblastoma proliferation and invasion.

High rates of recurrence and treatment resistance in the most common malignant adult brain cancer, glioblastoma (GBM), suggest that monotherapies are not sufficiently effective. Combination therapies are increasingly pursued, but the possibility of adverse drug-drug interactions may preclude clinical implementation. Developing single molecules with multiple targets is a feasible alternative strategy to identify effective and tolerable pharmacotherapies for GBM. Here, we report the development of a novel, first-in-class, dual aurora and lim kinase inhibitor termed F114. Aurora kinases and lim kinases are involved in neoplastic cell division and cell motility, respectively. Due to the importance of these cellular functions, inhibitors of aurora kinases and lim kinases are being pursued separately as anti-cancer therapies. Using in vitro and ex vivo models of GBM, we found that F114 inhibits GBM proliferation and invasion. These results establish F114 as a promising new scaffold for dual aurora/lim kinase inhibitors that may be used in future drug development efforts for GBM, and potentially other cancers.

Age-dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B.

A hallmark of advanced maternal age is a significant increase in meiotic chromosome segregation errors, resulting in early miscarriages and congenital disorders. These errors most frequently occur during meiosis I (MI). The spindle assembly checkpoint (SAC) prevents chromosome segregation errors by arresting the cell cycle until proper chromosome alignment is achieved. Unlike in mitosis, the SAC in oocytes is desensitized, allowing chromosome segregation in the presence of improperly aligned chromosomes. Whether SAC integrity further deteriorates with advancing maternal age, and if this decline contributes to increased segregation errors remains a fundamental question. In somatic cells, activation of the SAC depends upon Aurora kinase B (AURKB), which functions to monitor kinetochore-microtubule attachments and recruit SAC regulator proteins. In mice, oocyte-specific deletion of AURKB (Aurkb cKO) results in an increased production of aneuploid metaphase II-arrested eggs and premature age-related infertility. Here, we aimed to understand the cause of the short reproductive lifespan and hypothesized that SAC integrity was compromised. In comparing oocytes from young and sexually mature Aurkb cKO females, we found that SAC integrity becomes compromised rapidly with maternal age. We show that the increased desensitization of the SAC is driven by reduced expression of MAD2, ZW10 and Securin proteins, key contributors to the SAC response pathway. The reduced expression of these proteins is the result of altered protein homeostasis, likely caused by the accumulation of reactive oxygen species. Taken together, our results demonstrate a novel function for AURKB in preserving the female reproductive lifespan possibly by protecting oocytes from oxidative stress.

RNA-binding protein RNPC1 acts as an oncogene in gastric cancer by stabilizing aurora kinase B mRNA.

BACKGROUND: RNPC1 is reported to act as a tumor suppressor by binding and regulating the expression of target genes in various cancers. However, the role of RNPC1 in gastric cancer and the underlying mechanisms are still unclear. METHODS: Gastric cancer cells were stably transfected with lentivirus. Proliferation, migration, invasion, cell cycle in vitro and tumorigenesis in vivo were used to assess the role of RNPC1. Quantitative real-time PCR, western blotting and immunohistochemistry were used to detect the relationship between RNPC1 and aurora kinase B (AURKB). RNA immunoprecipitation (RIP), RNA electrophoretic mobility shift assays (REMSAs), and dual-luciferase reporter assays were used to identify the direct binding sites of RNPC1 with AURKB mRNA. A CCK-8 assay was conducted to confirm the function of AURKB in RNPC1-induced growth promotion. RESULTS: High RNPC1 expression was found in gastric cancer tissues and cell lines and was associated with high TNM stage. RNPC1 overexpression significantly promoted the proliferation, migration, and invasion of gastric cancer cells. Knockdown of RNPC1 could impede gastric cancer tumorigenesis in nude mice. AURKB expression was positively related to RNPC1. RNPC1 directly binds to the 3'-untranslated region (3'-UTR) of AURKB and enhances AURKB mRNA stability. AURKB reversed the proliferation induced by RNPC1 in gastric cancer cells. RNPC1 resulted in mitotic defects, aneuploidy and chromosomal instability in gastric cancer cells, similar to AURKB. CONCLUSION: RNPC1 acts as an oncogene in gastric cancer by influencing cell mitosis by increasing AURKB mRNA stability, which may provide a potential biomarker and a therapeutic target for gastric cancer.