Aurora Kinase A Promotes Ovarian Tumorigenesis through Dysregulation of the Cell Cycle and Suppression of BRCA2

Yang, Gong; Chang, Bin; Yang, Fan; Guo, Xiaoqing; Cai, Kathy Q.; Xiao, Xue; Wang, Huamin; Sen, Subrata; Hung, Mien‐Chie; Mills, Gordon B.; Chang, Sandy; Multani, Asha S.; Mercado‐Uribe, Imelda; Liu, Jinsong

doi:10.1158/1078-0432.ccr-09-3171

Cited by 111 publications

(127 citation statements)

References 46 publications

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“…In line with cell cycle arrest by TP58 in the in vitro study, results from microarray analyses revealed that cell cycle signaling consisting of 16 differentially expressed genes, interacting with each other was the top one pathway affected by TP58. This was also consistent with the role of cell cycle arrest of other Aurora kinase inhibitors (25,26).…”

Section: Discussionsupporting

confidence: 87%

Molecular mechanism of hepatocellular carcinoma-specific antitumor activity of the novel thienopyridine derivative TP58

Huang

Guo

et al. 2012

Oncol Rep

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Abstract. Despite progress made in the treatment of hepatocellular carcinoma (HCC), there is no curable treatment. Novel therapies are therefore needed. In our previous study on the design and synthesis of a small molecular inhibitor targeting Aurora kinase, we discovered a novel thienopyridine derivative compound (1g, TP58) which displayed the most potent and relatively specific inhibition of the proliferation of HepG2 human hepatoma cells in vitro. However, the molecular mechanism remains to be elucidated. Herein, in vitro and in vivo studies were conducted to further verify its antitumor activity against HCC. cDNA microarray and two-dimensional protein gel electrophoresis technology were utilized to elucidate the mechanism of HCC-specific inhibition of TP58. Flow cytometry analysis displayed that TP58 can significantly induce G0/ G1 arrest in HepG2 cells. Sixteen genes involved in cell cycle regulation were found to be dysregulated following TP58 treatment using microarray technology. Nine proteins whose expression was altered (corresponding to 10 spots identified as differentially expressed) were identified by proteomic analysis. Further study showed that TP58 can modulate the expression of some liver-enriched transcription factors (LETFs) and liverspecific marker genes, such as hepatic nuclear factor (HNF-4) and α-fetoprotein (AFP). These findings may help explain the mechanism of HCC-specific antitumor activity of TP58 and provide some useful insight for anti-HCC drug design and future use of thienopyridine derivatives in HCC therapy. IntroductionHepatocellular carcinoma (HCC), a major form of malignancy of liver with a worldwide increasing incidence, is one of the most common causes of cancer-related deaths in the world (1). The potential curative therapeutic options are surgical procedures, such as liver transplantation and surgical resection. Unfortunately, the majority (>80%) of the patients with advanced and unresectable HCC are not eligible for these techniques (2). Chemotherapy is one of the most commonly used treatment option, especially for patients with unresectable tumors. However, the use of conventional cytotoxic drugs has shown no improvement in survival, and patients suffer some adverse effects (3). Therefore, development of novel adjuvant therapies targeting liver cancer growth is essential.The Aurora kinase, a family of highly conserved serinethreonine kinases, consisting of three isoforms (Aurora A, Aurora B and Aurora C), have integral functions in mitotic cell division, tumor development and prognosis (4,5). Overexpression and amplification of Aurora A in HCC have been found to be correlated with high grade and high stage tumors (6). It has been reported that Aurora B is not only associated with hepatocellular carcinoma (HCC) recurrence (7) but with independent molecular marker predicting tumor invasiveness and poor prognosis of HCC (8). More recent studies have shown that the administration of small molecule inhibitors of Aurora kinases resulted in significant tumor growth inhibition t...

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Section: Discussionsupporting

confidence: 87%

Molecular mechanism of hepatocellular carcinoma-specific antitumor activity of the novel thienopyridine derivative TP58

Huang

Guo

et al. 2012

Oncol Rep

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“…[42][43][44][45] A large body of literature has proven that the overexpression of Aurora kinases causes the override of mitotic checkpoints in human cancers. 12,[46][47][48][49] Given the Aurora kinases' pivotal roles in the mitotic process during cell cycle, their over-expressions in malignancies and their crosstalk with tumor suppressors and oncogenic signaling pathways, small molecules targeting the Aurora kinases have attracted intense attention in the field of tumor therapy. 19,50 VX680 is a potent and selective inhibitor that targets both the Aurora A and B kinases and has demonstrated significant potential as an anti-cancer agent.…”

Section: Discussionmentioning

confidence: 99%

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

Jin

Zhang

et al. 2016

Cancer Biology & Therapy

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VX680 is a potent and selective inhibitor that targets the Aurora kinase family. The p38 mitogen-activated protein kinase (MAPK) regulates a large number of cellular pathways and plays an important role in the regulation of cell survival and apoptosis. This study aimed to evaluate the effect of VX680 on cervical cancer cells and investigate whether the effects on apoptosis are enhanced by the ablation of p38 MAPK activation. The results suggested that VX680 inhibited the proliferation of cervical cancer cells by causing G2/M phase arrest and endoreduplication and that the apoptotic effect was attenuated by the activation of p38 MAPK. However, the addition of BIRB796, which is an important p38 MAPK inhibitor, effectively eliminated the expression of p-p38 and hence significantly enhanced the cell death induced by VX680 in vitro. Further study demonstrated that BIRB796 cooperated with VX680 to suppress cervical cancer cell growth in a mouse xenograft model. Taken together, our results demonstrated that VX680 induced cell cycle arrest and endoreduplication in human cervical cancer cells. Combined treatment with VX680 and BIRB796 synergistically inhibited tumor growth both in vitro and in vivo. Dual blockade of Aurora kinases and p38 MAPK is therefore a promising strategy for cervical cancer treatment.

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“…In ovarian cancer cells, RNAi-mediated depletion of AURKA limits genomic instability, centrosome amplification and in vivo tumorigenic potential. 43 Thus, AURKA might function as an oncoprotein.…”

Section: Mitotic Deregulation As a Generator Of Tetraploidy And Tumormentioning

confidence: 99%

Illicit survival of cancer cells during polyploidization and depolyploidization

et al. 2010

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Tetraploidy and the depolyploidization of tetraploid cells may contribute to oncogenesis. Several mechanisms have evolved to avoid the generation, survival, proliferation and depolyploidization of tetraploids. Cells that illicitly survive these checkpoints are prone to chromosomal instability and aneuploidization. Along with their replication, tetraploids constantly undergo chromosomal rearrangements that eventually lead to pseudodiploidy by two non-exclusive mechanisms: (i) multipolar divisions and (ii) illicit bipolar divisions in the presence of improper microtubule-kinetochore attachments. Here, we describe the regulation and the molecular mechanisms that underlie such a 'polyploidization-depolyploidization' cascade, while focusing on the role of oncogenes and tumor suppressor genes in tetraploidy-driven tumorigenesis. We speculate that the identification of signaling/metabolic cascades that are required for the survival of tetraploid or aneuploid (but not diploid) cancer cells may pave the way for the development of novel broad-spectrum anticancer agents.

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Aurora Kinase A Promotes Ovarian Tumorigenesis through Dysregulation of the Cell Cycle and Suppression of BRCA2

Cited by 111 publications

References 46 publications

Molecular mechanism of hepatocellular carcinoma-specific antitumor activity of the novel thienopyridine derivative TP58

Molecular mechanism of hepatocellular carcinoma-specific antitumor activity of the novel thienopyridine derivative TP58

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

Illicit survival of cancer cells during polyploidization and depolyploidization

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