Aurora-A在乳腺癌致瘤机制和预后方面的研究进展

Aurora激酶参与中心体、微管功能调节,对细胞周期G2/M转换起重要作用.Aurora-A高表达可以引起中心体扩增、异倍体甚至肿瘤,是一个癌基因.Aurora激酶与乳腺癌的关系比较密切.本文综述了Aurora激酶通过p53基因、BRCA1基因、PTEN/PI3K/AKT信号通路、Aurora基因多态性、雌激素等因素相互作用参与乳腺肿瘤形成,并分析Aurora激酶在乳腺癌中的表达及与预后的关系.     

Aurora激酶与消化道肿瘤关系的研究进展

Aurora激酶是一类高度进化保守的丝/苏氨酸激酶,包括Aurora-A、Aurora-B、Aurora-C亚型,在细胞周期中呈动态分布,通过调控细胞有丝分裂过程中中心体的成熟和分离、双极纺锤体组装和稳定、染色体精确分离及细胞质有效分裂等过程,确保细胞周期正常完成。近年来研究者已在人体多种实体瘤中发现Aurora激酶过表达,高表达的Aurora激酶导致异常的有丝分裂,引起基因的不稳定性,与肿瘤的发生、增殖、预后密切相关,表明其是一种新型抗肿瘤靶点。目前Aurora激酶抑制剂是分子靶向治疗的新领域,部分抑制剂已进入临床试验,表现出较强的抗肿瘤活性。本文就Aurora激酶生物学特性及其抑制剂与消化道肿瘤发生发展的关系进行综述。     

Aurora A激酶研究进展

Aurora A激酶是进化上保守的有丝分裂丝／苏氨酸激酶Aurora激酶家族成员之一，在细胞内随细胞周期的变化呈动态分布，它广泛的参与了细胞周期不同阶段的各种事件，并在人类多种恶性肿瘤的发生发展过程中起到了至关重要的作用，因而很有可能成为一个极具前途的恶性肿瘤的分子治疗靶点。     

Aurora A激酶研究进展

Aurora A激酶是进化上保守的有丝分裂丝/苏氨酸激酶Aurora激酶家族成员之一,在细胞内随细胞周期的变化呈动态分布,它广泛的参与了细胞周期不同阶段的各种事件,并在人类多种恶性肿瘤的发生发展过程中起到了至关重要的作用,因而很有可能成为一个极具前途的恶性肿瘤的分子治疗靶点。     

肿瘤的细胞周期治疗

肿瘤细胞周期治疗时代已经来临。直接调节细胞周期的蛋白如细胞周期素依赖性激酶（CDKs）、检查点激酶（CHK）、Aurora激酶、Polo样激酶和WEE1激酶是细胞周期治疗药物的主要靶标。除了阻滞细胞周期从G1期进入S期外,细胞周期治疗还能够激活抗肿瘤免疫、控制代谢功能和调节转录水平。细胞周期治疗与激素药物、磷脂酰肌醇-3激酶（PI3K）抑制剂、表皮生长因子（EGFR）抑制剂和自噬抑制剂的联合应用提高了肿瘤内科治疗的效果。在整合基因组学时代,细胞周期治疗为肿瘤精准治疗增加了新内容。本文对肿瘤细胞周期治疗的主要靶标和作用机制进行综述。      

Aurora激酶与肿瘤的相关性

Aurora激酶家族为丝/苏氨酸蛋白激酶,在有丝分裂的染色体排列、分离和胞质分裂中起重要作用.Aurora激酶在人类实体瘤和血液肿瘤中过表达,在肿瘤细胞中表达异常会干扰有丝分裂中检控点的功能,可能导致遗传的不稳定和诱发肿瘤的形成.     

Aurora A反义寡核苷酸对人肺癌细胞系A549细胞生长与细胞周期的影响

目的：探讨Aurora A基因表达的下调对肺癌细胞生长和细胞周期分布的影响。方法：用脂质体瞬时转染法介导Aurora A反义硫代磷酸寡核苷酸（antisense oligodeoxynucleotides,ASODN）处理肺腺癌A549细胞,RT-PCR及Western-blot方法检测Aurora A mRNA和蛋白表达,流式细胞仪检测细胞周期分布的变化,四氮唑盐法（MTT）检测转染前后细胞生长抑制率变化。结果：Aurora A反义寡核苷酸作用于A549细胞后,细胞的生长抑制率在一定范围内呈剂量和时间依赖性,其中48h的IC50值约为300nmol/L,在此浓度和时间下,Aurora A反义寡核苷酸可明显降低Aurora A mRNA和蛋白的表达,且细胞周期阻滞于G2/M期和S期。结论：下调Aurora A表达可抑制肺腺癌细胞系A549的增殖,同时导致细胞阻滞于G2/M期及S期。     

Aurora—A激酶与恶性肿瘤研究进展

Aurora—A是Aurora激酶家族的重要成员之一，在细胞有丝分裂过程中发挥重要作用，其编码基因已被认为是一种新的癌基因。现综述目前在Aurora—A的结构和功能、细胞周期中mRNA水平、蛋白水平、激酶活性变化的分子机制、转录水平的调节等方面的研究进展，以及Aurora—A在恶性肿瘤的发生、扩增和表达、与临床病理特征和患者预后的关系及抗肿瘤治疗方面的研究进展。     

细胞周期调控基因与妇科恶性肿瘤

肿瘤细胞的基本特征是细胞生长失控和分化受阻.细胞生长和分化的调节与细胞周期中的诸多因素密切相关,因而出现了"癌症可能是一类细胞周期疾病"的观点[1].与细胞周期调节有关的分子有三类:细胞周期蛋白(cyclin)、细胞周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)、细胞周期蛋白依赖性激酶抑制蛋白(cyclin-dependent kinase inhibitor,CKI),这三类分子共同构成了细胞周期的网络调控系统cyxlins-CDKs-CKIs,这一系统中的调节基因及蛋白的改变和肿瘤发生、发展、治疗以及预后的关系,是目前国内外肿瘤研究的热点.本文就细胞周期的调节基因在妇科恶性肿瘤中的研究进展做一简要阐述.     

细胞周期相关激酶的肿瘤机制

细胞周期相关激酶(CCRK)作为一种新发现的细胞周期依赖激酶活化激酶,主要参与细胞周期的调控.相关研究证实CCRK在多种肿瘤细胞中均有过表达,且与患者不良预后密切相关,提示CCRK参与了肿瘤的发生发展过程.     

Effects of DNAzymes targeting Aurora kinase A on the growth of human prostate cancer

Aurora kinase A has been demonstrated to be involved in the malignant progression of many types of cancer including prostate cancer, we therefore hypothesized that Aurora kinase A might work as a valuable target for prostate cancer treatment. To test this hypothesis, we used DNAzyme technology to inhibit Aurora kinase A expression and evaluated the effects of DNAzymes as therapeutic agents to treat prostate cancer. In an in vitro cleavage assay, we found that a DNAzyme (DZ2) targeting Aurora kinase A could effectively cleave Aurora kinase A mRNA. When transfected into the prostate cancer cell line PC3, DZ2 was found to strongly inhibit the expression of Aurora kinase A examined by western blot analysis, and thus suppressed cell growth, arrested the progression of cell cycle, induced cell apoptosis and attenuated cell migration, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay, flow cytometry and Boyden chamber assay. Through in vivo study, we also found that DZ2 could significantly inhibit the growth of human prostate cancer xenografts in nude mice. In conclusion, DZ2 could effectively attenuate malignant progression of prostate cancer both in vitro and in vivo, suggesting that DNAzyme targeting Aurora kinase A may be used as a valuable therapy to treat prostate cancer.     

Mitotic Failures in Cancer: Aurora B Kinase and its Potential Role in the Development of Aneuploidy

One of the basic requirements during the process of cell division is to maintain genetic integrity and ensure normal ploidy. The family of Aurora kinases, composed of Aurora A, B and C, takes a major role in the control of centrosome cycle, mitotic entry, chromosome condensation and coordination of chromosomal movements. Deregulation of kinase expression was described in a series of different malignancies which was also associated with aneuploidy. Recently, Aurora kinases gained significant interest as potential therapeutic targets in oncology. While there is increasing evidence about the activities of Aurora A kinase during cancer progression, data are controversial regarding the role of Aurora B. In this review the biology of Aurora kinases and its potential relation to cancer progression is discussed with special focus on functional changes and determination of Aurora B kinase.     

Targeting aurora kinase with MK-0457 inhibits ovarian cancer growth

PURPOSE: The Aurora kinase family plays pivotal roles in mitotic integrity and cell cycle. We sought to determine the effects of inhibiting Aurora kinase on ovarian cancer growth in an orthotopic mouse model using a small molecule pan-Aurora kinase inhibitor, MK-0457. EXPERIMENTAL DESIGN: We examined cell cycle regulatory effects and ascertained the therapeutic efficacy of Aurora kinase inhibition both alone and combined with docetaxel using both in vitro and in vivo ovarian cancer models. RESULTS: In vitro cytotoxicity assays with HeyA8 and SKOV3ip1 cells revealed >10-fold greater docetaxel cytotoxicity in combination with MK-0457. After in vivo dose kinetics were determined using phospho-histone H3 status, therapy experiments with the chemosensitive HeyA8 and SKOV3ip1 as well as the chemoresistant HeyA8-MDR and A2780-CP20 models showed that Aurora kinase inhibition alone significantly reduced tumor burden compared with controls (P values<0.01). Combination treatment with docetaxel resulted in significantly improved reduction in tumor growth beyond that afforded by docetaxel alone (P 相似文献   

Aurora kinases as anticancer drug targets

The human aurora family of serine-threonine kinases comprises three members, which act in concert with many other proteins to control chromosome assembly and segregation during mitosis. Aurora dysfunction can cause aneuploidy, mitotic arrest, and cell death. Aurora kinases are strongly expressed in a broad range of cancer types. Aurora A expression in tumors is often associated with gene amplification, genetic instability, poor histologic differentiation, and poor prognosis. Aurora B is frequently expressed at high levels in a variety of tumors, often coincidently with aurora A, and expression level has also been associated with increased genetic instability and clinical outcome. Further, aurora kinase gene polymorphisms are associated with increased risk or early onset of cancer. The expression of aurora C in cancer is less well studied. In recent years, several small-molecule aurora kinase inhibitors have been developed that exhibit preclinical activity against a wide range of solid tumors. Preliminary clinical data from phase I trials have largely been consistent with cytostatic effects, with disease stabilization as the best response achieved in solid tumors. Objective responses have been noted in leukemia patients, although this might conceivably be due to inhibition of the Abl kinase. Current challenges include the optimization of drug administration, the identification of potential biomarkers of tumor sensitivity, and combination studies with cytotoxic drugs. Here, we summarize the most recent preclinical and clinical data and discuss new directions in the development of aurora kinase inhibitors as antineoplastic agents.     

Aurora kinase inhibition overcomes cetuximab resistance in squamous cell cancer of the head and neck

Squamous cell cancer of the head and neck (SCCHN) is the sixth leading cause for cancer deaths worldwide. Despite extense knowledge of risk factors and pathogenesis about 50 percent of all patients and essentially every patient with metastatic SCCHN eventually die from this disease. We analyzed the clinical data and performed immunohistochemistry for Epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurora-A) expression in 180 SCCHN patients. Patients characterized by elevated EGFR and elevated Aurora-A protein expression in tumor tissue represent a risk group with poor disease-free and overall survival (EGFR(low)Aurora-A(low) versus EGFR(high)Aurora-A(high), p = 0.024). Treating SCCHN cell lines with a pan-Aurora kinase inhibitor resulted in defective cytokinesis, polyploidy and apoptosis, which was effective irrespective of the EGFR status. Combined Aurora kinase and EGFR targeting using a monoclonal anti-EGFR antibody was more effective compared to single EGFR and Aurora kinase inhibition. Comparing pan-Aurora kinase and Aurora-A targeting hints towards a strong and clinically relevant biological effect mediated via Aurora kinase B. Taken together, our findings characterize a new poor risk group in SCCHN patients defined by elevated EGFR and Aurora-A protein expression. Our results demonstrate that combined targeting of EGFR and Aurora kinases represents a therapeutic means to activate cell cycle checkpoints and apoptosis in SCCHN.     

Expression of Aurora A (but not Aurora B) is predictive of survival in breast cancer

PURPOSE: The cell cycle mediators Aurora A and B are targets of drugs currently in clinical development. As with other targeted therapies in breast cancer, response to therapy might be associated with target expression in tumors. We therefore assessed expression of Aurora A and B in breast tumors and studied associations with clinical/pathologic variables. EXPERIMENTAL DESIGN: Tissue microarrays containing primary specimens from 638 patients with 15-year follow-up were employed to assess expression of Aurora A and B using our automated quantitative analysis method; we used cytokeratin to define pixels as breast cancer (tumor mask) within the array spot and measured Aurora A and B expression within the mask using Cy5-conjugated antibodies. RESULTS: Aurora A and B expression was variable in primary breast tumors. High Aurora A expression was strongly associated with decreased survival (P = 0.0005). On multivariable analysis, it remained an independent prognostic marker. High Aurora A expression was associated with high nuclear grade and high HER-2/neu and progesterone receptor expression. Aurora B expression was not associated with survival. CONCLUSIONS: Aurora A expression defines a population of patients with decreased survival, whereas Aurora B expression does not, suggesting that Aurora A might be the preferred drug target in breast cancer. Aurora A expression in early-stage breast cancer may identify a subset of patients requiring more aggressive or pathway-targeted treatment. Prospective studies are needed to confirm the prognostic role of Aurora A as well as the predictive role of Aurora A expression in patients treated with Aurora A inhibitors.