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.
Highlights
Mitosis controlling the mother cells to divide into two daughter cells with equal chromosomes and cytoplasm is accurately regulated by a series of serine/threonine kinases in cell cycle, and among which Aurora kinases are important and indispensable in multiple steps of mitotic progression
Given overexpression or gene amplification of Aurora kinases has been identified in diverse cancers, making them become potent targets of cancer therapy, a series of Aurora kinases inhibitors (AKIs) have been produced for the past decades and inhibition of expression or activity of Aurora kinases by AKIs suppresses cell proliferation, migration and invasion in cancer cells [29, 119, 120], inhibits the progress and growth of many cancers [95, 121, 122] as Figure 5 shown, and more exciting is that some AKIs have already been used into clinical trials [123,124,125,126,127,128,129,130,131,132,133,134,135,136] (Table 1)
Opyrchal M et al firstly demonstrated that AURKA activated SMAD5 oncogenic signaling pathway and thereby down-regulated estrogen receptor α (ERα), leading to estrogen resistance in ERα+ breast cancers and combination tamoxifen with MLN8237 abrogated the endocrine resistance [148]
Summary
Mitosis controlling the mother cells to divide into two daughter cells with equal chromosomes and cytoplasm is accurately regulated by a series of serine/threonine kinases in cell cycle, and among which Aurora kinases are important and indispensable in multiple steps of mitotic progression. AURKA could phosphorylate RASassociation domain family 1, isoform A (RASSF1A), a novel tumor suppressor, disrupt RASSF1A-mediated microtubules stabilization and M-phase cell cycle arrest, and lead to uncontrolled proliferation in cancers [69].
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