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Review
. 2017 Apr 4;8(14):23937-23954.
doi: 10.18632/oncotarget.14893.

Aurora kinases: novel therapy targets in cancers

Anqun Tang  1 , Keyu Gao  1 , Laili Chu  1 , Rui Zhang  1 , Jing Yang  1 , Junnian Zheng  1   2
Affiliations
Review

Aurora kinases: novel therapy targets in cancers

Anqun Tang et al. Oncotarget. .

Abstract

Aurora kinases, a family of serine/threonine kinases, consisting of Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), are essential kinases for cell division via regulating mitosis especially the process of chromosomal segregation. Besides regulating mitosis, Aurora kinases have been implicated in regulating meiosis. The deletion of Aurora kinases could lead to failure of cell division and impair the embryonic development. Overexpression or gene amplification of Aurora kinases has been clarified in a number of cancers. And a growing number of studies have demonstrated that inhibition of Aurora kinases could potentiate the effect of chemotherapies. For the past decades, a series of Aurora kinases inhibitors (AKIs) developed effectively repress the progression and growth of many cancers both in vivo and in vitro, suggesting that Aurora kinases could be a novel therapeutic target. In this review, we'll first briefly present the structure, localization and physiological functions of Aurora kinases in mitosis, then describe the oncogenic role of Aurora kinases in tumorigenesis, we shall finally discuss the outcomes of AKIs combination with conventional therapy.

Keywords: Aurora kinases; Aurora kinases inhibitors; cancer therapy target; combination therapy; mitosis.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Structure and cellular distribution of Aurora kinases in mitosis
A. Schematic drawing of AURKA, AURKB and AURKC proteins with indicated domains. B. Cellular localization shift of Aurora kinases in mitosis (AURKC is not shown due to the elusive cellular localization and function).
Figure 1
Figure 1. Structure and cellular distribution of Aurora kinases in mitosis
A. Schematic drawing of AURKA, AURKB and AURKC proteins with indicated domains. B. Cellular localization shift of Aurora kinases in mitosis (AURKC is not shown due to the elusive cellular localization and function).
Figure 2
Figure 2. Interaction of Aurora kinases and tumor suppressor p53
Both AURKA and AURKB can regulate p53 through directly or indirectly mechanisms as indicated above. Moreover, the p53 deficiency which is often shown in numerous cancers further contributes to the expression of Aurora kinases, facilitating tumor development.
Figure 3
Figure 3. Co-regulation of AURKA, BRCA and Ras in tumorigenesis
A. CHK2-BRCA1 axis suppress AURKA oncogenic function. B. AURKA inactivates Tumor suppressor BRCA1, leading to genomic instability and contributing to cell transformation. In addition, AURKA overexpression along with BRCA2 mutation facilitates the cell cycle via hyper-phosphorylating cell cycle kinase CDK. Imbalance between AURKA and BRCA2 could enhance Ras-mediated tumorigenesis.
Figure 3
Figure 3. Co-regulation of AURKA, BRCA and Ras in tumorigenesis
A. CHK2-BRCA1 axis suppress AURKA oncogenic function. B. AURKA inactivates Tumor suppressor BRCA1, leading to genomic instability and contributing to cell transformation. In addition, AURKA overexpression along with BRCA2 mutation facilitates the cell cycle via hyper-phosphorylating cell cycle kinase CDK. Imbalance between AURKA and BRCA2 could enhance Ras-mediated tumorigenesis.
Figure 4
Figure 4. The interaction of Myc and Aurora Kinases in tumorigenesis
AURKA can transcriptionally upregulates the expression of c-Myc. On the other hand, c-Myc also binds to promoter of AURKA and transcriptionally increases the expression of AURKA. Additionally, activated c-Myc up-regulates the expression of cyclin D2, cdk4 as well as cyclin-E, contributing to the formation of cyclin-E/cdk2 complex, phosphorylating p27Kip1 on Thr187, and consequently could provoke the cell proliferation and induce the Myc-mediated lymphomagenesis. c-Myc indirectly transcriptionally activate AURKB through unclear mechanisms. Besides, AURKA protects N-Myc from FBXW7-mediated degradation. High expression of AURKA and AURKB are implicated in tumorigenesis.
Figure 5
Figure 5. The model of AKIs targeting into several signaling pathways
Inhibition of Aurora kinases by AKIs could not only suppress the pro-oncogenic function, but also could block tumorigenesis via several signaling pathways.
See this image and copyright information in PMC

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