title: Aurora B confers cancer cell resistance to TRAIL-induced apoptosis via phosphorylation of survivin.
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.
authors.affiliation: Department of Molecular Science & Technology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon 443-749, Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Yoon
authors.forename: Seok Soon
authors.initials: SS
authors.lastname: Park
authors.forename: You Jung
authors.initials: YJ
authors.lastname: Kang
authors.forename: In Young
authors.initials: IY
authors.lastname: Kim
authors.forename: Ju Ahn
authors.initials: JA
authors.lastname: Lee
authors.forename: Jong Soo
authors.initials: JS
authors.lastname: Lee
authors.forename: Eu-Gene
authors.initials: EG
authors.lastname: Kim
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Lee
authors.forename: Kyeong Sook
authors.initials: KS
authors.lastname: Choi
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology; D053148:Caspase 3 / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D056945:Hep G2 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D009369:Neoplasms; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D001549:Benzamides; D051034:Inhibitor of Apoptosis Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3