Tumor necrosis factor-related apoptosis-induced
ligand (TRAIL) induces apoptosis selectively in
cancer cells while sparing normal cells. However, many
cancer cells are resistant to TRAIL-induced cell death. In this study, we examined whether Aurora B, which is frequently overexpressed in
cancer cells, is associated with TRAIL resistance. The
protein levels of Aurora B were higher in TRAIL-resistant
cancer cell lines than in TRAIL-sensitive
cancer cell lines. Exogenously expressed Aurora B attenuated TRAIL-induced apoptosis in the tested TRAIL-sensitive
cancer cell lines, whereas the
small interfering RNA-mediated suppression of Aurora B expression stimulated TRAIL-mediated apoptosis in the tested TRAIL-resistant
cancer cell lines. Furthermore, combined treatment with TRAIL and
ZM447439, a specific inhibitor of Aurora B, synergistically induced apoptosis in various TRAIL-resistant
cancer cells, suggesting that this combined regimen may represent an attractive strategy for effectively treating TRAIL-resistant malignant
cancers. Mechanistically, the inhibition of Aurora B activity in various
cancer cells commonly downregulated
survivin protein levels and potentiated the activation of
caspase-3. In addition, Aurora B inhibition induced mitotic catastrophe, which also contributed to the sensitization of cells to TRAIL-mediated apoptosis. Interestingly, forced overexpression of Aurora B increased the
protein levels of
survivin, but not those of a non-phosphorylatable
survivin mutant in which
threonine 117 was replaced by
alanine, indicating that phosphorylation of
survivin is required for this effect. Furthermore, TRAIL-induced apoptosis in MDA-MB-435S cells was attenuated by wild-type
survivin but not by the non-phosphorylatable
survivin mutant. Collectively, our results demonstrate that Aurora B confers TRAIL resistance to
cancer cells via phosphorylation of
survivin.