The Aurora kinase A inhibitor TC-A2317 disrupts mitotic progression and inhibits cancer cell proliferation

Abstract

Mitotic progression is crucial for the maintenance of chromosomal stability. A proper progression is ensured by the activities of multiple kinases. One of these enzymes, the serine/threonine kinase Aurora A, is required for proper mitosis through the regulation of centrosome and spindle assembly. In this study, we functionally characterized a newly developed Aurora kinase A inhibitor, TC-A2317. In human lung cancer cells, TC-A2317 slowed proliferation by causing aberrant formation of centrosome and microtubule spindles and prolonging the duration of mitosis. Abnormal mitotic progression led to accumulation of cells containing micronuclei or multinuclei. Furthermore, TC-A2317–treated cells underwent apoptosis, autophagy or senescence depending on cell type. In addition, TC-A2317 inactivated the spindle assembly checkpoint triggered by paclitaxel, thereby exacerbating mitotic catastrophe. Consistent with this, the expression level of Aurora A in tumors was inversely correlated with survival in lung cancer patients. Collectively, these data suggest that inhibition of Aurora kinase A using TC-A2317 is a promising target for anti-cancer therapeutics.

Activation of S6 signaling is associated with cell survival and multinucleation in hyperplastic skin after epidermal loss of AURORA-A Kinase

“…6a). Although VX680 inhibits the AURORA Kinase family and TC-A2317 is more selective for AUR-A [49], both inhibitors produced enlarged cells, indicative of mitotic arrest and slippage ( Fig. 6b and Supplementary Figure 8a-b).…”

Elevated mRNA Levels of AURKA, CDC20 and TPX2 are associated with poor prognosis of smoking related lung adenocarcinoma using bioinformatics analysis

“…The interplay between epidermal growth factor receptor ( EGFR ) and AURKA maybe could provide a new treatment target for lung cancer patients carrying EGFR mutations 26. The inhibitor of AURKA can suppress the cell proliferation in lung cancer cells 27 and the elevated expression of CDC20 can predict the poor prognosis in lung cancer patients, or even in lung adenocarcinoma patients 28,29. High level of CDC20 expression was associated with poor prognosis in many cancers in addition to lung cancer 30-32, and it was correlated with tumor grade and stage 33.…”

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

“…Genetic depletion or pharmacological inhibition of Aurora A and B results in aberrant cell division . Suppression of Aurora A induces formation of monopolar spindles and aneuploidy, including multinucleation and micronucleation . Suppression of Aurora B induces formation of multipolar spindles and failure of cytokinesis, leading to multinucleation .…”