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  • Roles of Aurora kinases in directly activating

    2024-05-14

    Roles of Aurora kinases in directly activating multiple oncogenic pathways and promoting proliferation as well as transformation have also been demonstrated. Aurora-A has been shown to up-regulate telomerase reverse transcriptase mRNA through c-myc [26]. The kinase was also implicated in activating the Akt pathway and directly phosphorylate GSK3β leading to activation of the β-catenin–TCF transcription complex [27] underscoring the involvement of Aurora-A in this oncogenic pathway. Additionally, positive regulation of NF-κB signaling has been demonstrated as a consequence of Aurora-A mediated IκBα phosphorylation leading to activation of the NF-κB complexes [28]. Interestingly, IκB kinase2, a component BAMB-4 of the IκK complex responsible for physiologic phosphorylation and degradation of IκB appears to negatively regulate the stability of Aurora-A protein and thus has a role in bipolar spindle assembly [29]. These findings support the notion that under normal physiological conditions IκB kinase2 positively regulates NF-κB but antagonizes Aurora-A signaling to ensure proper mitotic assembly and chromosome segregation while over expression of Aurora-A leads to derangement of this regulatory network. Furthermore, oncogenic effects of Aurora-A is also mediated through phosphorylation of RalA in the Ras signaling pathway [30], [31] and the tumor suppressor NORE1A that functions as a regulatory node between Ras signaling and microtubule nucleation [32]. Gain of function of Aurora-A, therefore, appears to be a seminal defect in cancer BAMB-4 that can cause dual problems of aberrantly activating the Ras and the NF-κB signaling and also induction of abnormal mitotic spindle assembly. Finally, a kinase activity independent role of Aurora-A in N-Myc amplified neuroblastoma tumors, showing frequent amplification of Aurora-A was revealed that involved stabilization of the oncogenic N-Myc protein [33]. Intriguingly, though, an Aurora-A inhibitor has demonstrated broad and unprecedented robust antitumor activity in all neuroblastomas in N-Myc independent manner [34]. These findings implicating Aurora-A's pleiotropic role in regulating mitotic cell division cycle and multiple oncogenic signaling networks justify the current interest in developing effective Aurora kinase inhibitors for anticancer therapy. Future work will determine if the currently developed ATP-competitive kinase activity inhibitors alone or in combination with allosteric inhibitors interfering with Aurora kinase binding proteins would be required to achieve maximal efficacy in the treatment of human cancers.
    Aurora kinase inhibitors Given their pivotal roles in mitotic process during cell cycle, over expression in malignancy and cross talks with tumor suppressor as well as oncogenic signaling pathways, members of the Aurora kinase family have emerged as promising chemotherapeutic targets for cancer. As indicated earlier, the in vivo target selectivity of Aurora kinases for cancer cells is proposed because these proteins express preferentially only in progressively proliferating cells [35]. Supporting this idea, early in vitro experiments of Aurora kinase inhibitor ZM447439 demonstrated selective loss of viability only of rapidly dividing cells while the non-dividing cells remained viable [36]. A number of Aurora kinase inhibitors displaying differential IC50 values toward the three family members have since then been developed and utilized to dissect the functional role of Aurora kinases in mitotic progression. Antitumor activities of these inhibitors have also been evaluated in preclinical studies and a few of them have progressed to early stage clinical trials for treatment of different types of cancers. In this section, we present an overview of the biological effects of Aurora kinase inhibitors on mitotic processes and the signaling pathways based on the available published literature (Table 2). For detailed information on the results of Aurora kinase inhibitors in clinical trials readers may refer to recent reviews written on the subject [37], [38].