Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis

Tatsuka, Masaaki; Sato, Sunao; Kitajima, Shojiro; Suto, Shiho; Kawai, Hidehiko; Miyauchi, Mutsumi; Ogawa, Ikuko; Maeda, Masako; Ota, Takayo; Takata, Takashi

doi:10.1038/sj.onc.1208293

Cited by 94 publications

(83 citation statements)

References 21 publications

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“…In fact, overexpression of Aurora-A potentiates the oncogenic action of RAS, known to be implicated in human thyrocytes transformation and chromosome instability in thyroid cancer. 42 Furthermore, it has been shown that p53 may bind to the catalytic domain of Aurora-A and suppress its ability to induce centrosome amplification. 43 On the other hand, it has been documented that p53 is a substrate of Aurora-A and its phosphorylation on Ser215 leads to the inhibition of the p53 transactivating action on several genes.…”

Section: Discussionmentioning

confidence: 99%

Expression of Aurora kinases in human thyroid carcinoma cell lines and tissues

Ulisse

Delcros²,

Baldini

et al. 2006

Intl Journal of Cancer

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The Aurora kinases are involved in the regulation of cell cycle progression, and alterations in their expression have been shown to associate with cell malignant transformation. In the present study, we demonstrated that human thyrocytes express all 3 Aurora kinases (A, B and C) at both protein and mRNA level and this expression is cell cycle-regulated. An increase in the protein level of the 3 kinases was found, with respect to normal human thyrocytes (HTU5), in the human cell lines derived from follicular (FTC-133), papillary (B-CPAP) and anaplastic (8305C) thyroid carcinomas, but not in cells derived from a follicular adenoma (HTU42). These observations were mirrored in RT-PCR experiments for Aurora-A and B. In contrast, Aurora-C mRNA levels were not significantly different among the different cell types analyzed, suggesting that posttranscriptional mechanism(s) modulate its expression. The expression at the protein level of all 3 Aurora kinases was significantly higher in 3 thyroid papillary carcinomas with respect to normal matched tissues obtained from the same patients. Similar modifications, at the mRNA level, could be observed in 7 papillary carcinoma tissues for Aurora-A and B, but not for Aurora-C. In conclusion, we demonstrated that normal human thyrocytes express all 3 members of the Aurora kinase family, and their expression is amplified in malignant thyroid cell lines and tissues. These results suggest that the Aurora kinases may play a relevant role in malignant thyroid cancers, and may represent a putative therapeutic target for thyroid neoplasms

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Section: Discussionmentioning

confidence: 99%

Expression of Aurora kinases in human thyroid carcinoma cell lines and tissues

Ulisse

Delcros²,

Baldini

et al. 2006

Intl Journal of Cancer

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“…The Aurora A gene is located at chromosome position 20q13, a site frequently amplified in breast and colorectal tumors (Bischoff et al, 1998;Zhou et al, 1998;Bischoff and Plowman, 1999). Overexpression of Aurora A has been reported in many tumor cells (Miyoshi et al, 2001;Goepfert et al, 2002;Tatsuka et al, 2005). In vitro studies revealed multiple mitotic abnormalities after Aurora A overexpression, including nonfunctional bipolar spindle , cytokinesis failure, polyploidy (Meraldi et al, 2002), and centrosome amplification (Miyoshi et al, 2001;Marumoto et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Id1 Overexpression Induces Tetraploidization and Multiple Abnormal Mitotic Phenotypes by Modulating Aurora A

Man¹,

Rosa

Yip³

et al. 2008

MBoC

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The basic helix-loop-helix transcription factor, Id1, was shown to induce tetraploidy in telomerase-immortalized nasopharyngeal epithelial cells in this study. Using both transient and stable Id1-expressing cell models, multiple mitotic aberrations were detected, including centrosome amplification, binucleation, spindle defects, and microtubule perturbation. Many of these abnormal phenotypes have previously been reported in cells overexpressing Aurora A. Further experiments showed that Id1 could stabilize Aurora A, whereas knocking down Aurora A expression in Id1-expressing cells could rescue some of the mitotic defects. The mechanisms by which Aurora A could be modulated by Id1 were explored. DNA amplification of the Aurora A locus was not involved. Id1 could only weakly activate the transcriptional activity of the Aurora A promoter. We found that Id1 overexpression could affect Aurora A degradation, leading to its stabilization. Aurora A is normally degraded from mitosis exit by the APC/C Cdh1 -mediated proteasomal proteolysis pathway. Our results revealed that Id1 and Cdh1 are binding partners. The association of Id1 and Cdh1 was found to be dependent on the canonical destruction box motif of Id1, the increased binding of which may compete with the interaction between Cdh1 and Aurora A, leading to stabilization of Aurora A in Id1-overexpressing cells.

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“…The phenotypic differences on the selective inhibition of Aurora-A, inhibition of both Aurora-A and Aurora-B, or the selective inhibition of Aurora-B suggest that selectively targeting Aurora-A or Aurora-B may provide different therapeutic outcomes and/or safety profiles (14). Aurora-A is associated with tumorigenesis (15)(16)(17)(18)(19)(20). Overexpression of Aurora-A is frequently observed in multiple tumor types and is correlated with poor prognosis (1).…”

Section: Introductionmentioning

confidence: 99%

MK-5108, a Highly Selective Aurora-A Kinase Inhibitor, Shows Antitumor Activity Alone and in Combination with Docetaxel

Shimomura¹,

Hasako²,

Nakatsuru³

et al. 2010

Molecular Cancer Therapeutics

123

108

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Aurora-A kinase is a one of the key regulators during mitosis progression. Aurora-A kinase is a potential target for anticancer therapies because overexpression of Aurora-A, which is frequently observed in some human cancers, results in aberrant mitosis leading to chromosomal instability and possibly tumorigenesis. MK-5108 is a novel small molecule with potent inhibitory activity against Aurora-A kinase. Although most of the Aurora-kinase inhibitors target both Aurora-A and Aurora-B, MK-5108 specifically inhibited Aurora-A kinase in a panel of protein kinase assays. Inhibition of Aurora-A by MK-5108 in cultured cells induced cell cycle arrest at the G2-M phase in flow cytometry analysis. The effect was confirmed by the accumulation of cells with expression of phosphorylated Histone H3 and inhibition of Aurora-A autophosphorylation by immunostaining assays. MK-5108 also induced phosphorylated Histone H3 in skin and xenograft tumor tissues in a nude rat xenograft model. MK-5108 inhibited growth of human tumor cell lines in culture and in different xenograft models. Furthermore, the combination of MK-5108 and docetaxel showed enhanced antitumor activities compared with control and docetaxel alone–treated animals without exacerbating the adverse effects of docetaxel. MK-5108 is currently tested in clinical trials and offers a new therapeutic approach to combat human cancers as a single agent or in combination with existing taxane therapies. Mol Cancer Ther; 9(1); 157–66

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Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis

Cited by 94 publications

References 21 publications

Expression of Aurora kinases in human thyroid carcinoma cell lines and tissues

Expression of Aurora kinases in human thyroid carcinoma cell lines and tissues

Id1 Overexpression Induces Tetraploidization and Multiple Abnormal Mitotic Phenotypes by Modulating Aurora A

MK-5108, a Highly Selective Aurora-A Kinase Inhibitor, Shows Antitumor Activity Alone and in Combination with Docetaxel

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