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Aurora B confers cancer cell resistance to TRAIL-induced apoptosis via phosphorylation of survivin

Authors
Yoon, MJ | Park, SS | Kang, YJ | Kim, IY | Lee, JA | Lee, JS | Kim, EG | Lee, CW | Choi, KS
Citation
Carcinogenesis, 33(3). : 492-500, 2012
Journal Title
Carcinogenesis
ISSN
0143-33341460-2180
Abstract
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.
MeSH

DOI
10.1093/carcin/bgr298
PMID
22159225
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Ajou Authors
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