Journal Article

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

Mi Jin Yoon, Seok Soon Park, You Jung Kang, In Young Kim, Ju Ahn Lee, Jong Soo Lee, Eu-Gene Kim, Chang-Woo Lee and Kyeong Sook Choi

in Carcinogenesis

Volume 33, issue 3, pages 492-500
Published in print March 2012 | ISSN: 0143-3334
Published online December 2011 | e-ISSN: 1460-2180 | DOI:
Aurora B confers cancer cell resistance to TRAIL-induced apoptosis via phosphorylation of survivin

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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.

Journal Article.  7601 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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