Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy

Abstract

The Aurora kinase family comprises three serine/threonine kinases, Aurora-A, -B and -C. Among these, Aurora-A and -B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases have been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis.Aurora kinases therefore represent promising targets for anticancer therapeutics. So far, a number of Aurora kinase inhibitors (AKIs) have been generated, of which some are currently undergoing clinical trials. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in contributing tumorigenesis, the recent preclinical and clinical AKI data and potential alternative routes for Aurora-A kinase inhibition.Key words: Aurora-A; Aurora kinase inhibitors (AKIs); targeted cancer therapy; mitosis; tumorigenesis 3 In mammals, the Aurora family of serine/threonine kinases consists of Aurora-A, -B and -C, which share a highly conserved catalytic domain containing auto-phosphorylating sites. The catalytic domain is flanked by a very short C-terminal tail and an N-terminal domain of variable lengths 1,2 . In the C-terminal regions of Auroras, there exists a short amino-acid peptide motif called "destruction box" (D-box). The D-box is recognized by the anaphase-promoting complex/cyclosome (APC/C) for degradation through the ubiquitin/proteasome-dependent pathway ( Fig. 1A). Despite their structural similarities, the expression patterns, cellular localization and physiological functions of these three Aurora kinases are largely distinct.Aurora-A and -B are commonly expressed in most cell types whereas Aurora-C is specially expressed in the testis. Both Aurora-A and -B play key roles in regulating cell-cycle progression from G2 through to cytokinesis. Aurora-C has a unique physiological role in spermatogenesis and functions as a chromosomal passenger protein similar to Aurora-B in mitosis 2 .Overexpression of Aurora-A and -B have been found in multiple types of cancer (Table 1), which function as oncogenes to promote tumorigenesis, providing potential targets for cancer therapy.However, comparatively little information is available regarding the roles of Aurora-C in cancer.In this review, we will focus on recent progress as well as the main unresolved issues associated with Aurora-A in cancer.4 1 FUNCTIONS OF AURORA-A In normal cells a. MitosisIn G1 phase, the level of Aurora-A is rarely detectable. During S phase, a small proportion of Aurora-A is first detected at centrosomes. At late G2 phase, Aurora-A accumulates evidently at centrosomes and becomes activated 3 . During prometaphase and metaphase, active Aurora-A localizes on bipolar spindles and spindle poles after...

Aurora kinases: novel therapy targets in cancers

“…In a feedback loop, p53 inhibits AURKA via both transcriptional and posttranscriptional regulation [95]. Silencing of p53 increases Cdk2 activity by reducing p21 wAF1/CIP1 expression, in turn Cdk2 phosphorylates Rb1 and dissociates E2F3, which then promotes AURKA expression via binding to its gene promoter [95].…”

“…Silencing of p53 increases Cdk2 activity by reducing p21 wAF1/CIP1 expression, in turn Cdk2 phosphorylates Rb1 and dissociates E2F3, which then promotes AURKA expression via binding to its gene promoter [95]. In addition, Mutant p53 or loss of p53 functions causes elevated expression of miR-25 expression and leads to a decreased in level of F-box and WD repeat-containing 7 (FBXW7), a E3 ubiquitin ligase and well-known tumor suppressor, resulting in AURKA overexpression [96].…”

“…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 AKIs have been produced for the past decades and inhibition of expression or activity of Aurora kinases by AKIs indeed 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 [123–136] (Table 1). Based on current researches and observations, MLN8237 (Alisertib), one of AURKA selective inhibitor, and the AURKB selective inhibitor AZD1152 are successfully attracted researchers attention and are undergoing III clinical trials due to their potential dominant suppression for cancer treatment [125, 127].…”

An Aurora kinase inhibitor, AMG900, inhibits glioblastoma cell proliferation by disrupting mitotic progression

“…9,11 In fact, Aurora kinases are highly overexpressed in diverse cancers. [12][13][14] Therefore, inhibiting Aurora kinases may be an effective cancer strategy. Numerous Aurora inhibitors have been developed; these include selective Aurora A inhibitors such as alisertib/ MLN8237, MK-5108/VX-689, MLN8054, and TC-A 2317; selective Aurora B inhibitors such as barasertib/AZD1152 and hesperadin; and pan-Aurora inhibitors such as AMG900, AS703569/R-763, CCT137690, danusertib/PHA-739358, SNS-314, VE-465, and VX-680/MK-0457/tozasertib.…”

Unraveling the role of aurora A beyond centrosomes and spindle assembly: implications in muscle differentiation

“…AurkA is well documented in several biologic processes, including centrosome duplication and bipolar spindle assembly during chromosomal segregation (1). Hence, deregulation in AurkA phosphorylation cascade across mitosis is closely linked to tumorigenesis (2,3). The somatic members of Aurk A and B are often overexpressed in multiple cancers and have been potential targets for anticancer drug development.…”