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: Mi Jin Yoon, Seok Soon Park, You Jung Kang, In Young Kim, Ju Ahn Lee, Jong Soo Lee, Eu-Gene Kim, Chang-Woo Lee, Kyeong Sook Choi
• Journal: Carcinogenesis (Carcinogenesis) Vol. 33 Issue 3 Pg. 492-500 (Mar 2012) ISSN: 1460-2180 [Electronic] England
• PMID: 22159225 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline
• Apoptosis Regulatory Proteins
• BIRC5 protein, human
• Benzamides
• Inhibitor of Apoptosis Proteins
• Quinazolines
• RNA, Small Interfering
• Survivin
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• AURKB protein, human
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Caspase 3

Topics

• Apoptosis
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Aurora Kinase B
• Aurora Kinases
• Benzamides (pharmacology)
• Caspase 3 (biosynthesis, metabolism)
• Cell Line, Tumor
• Hep G2 Cells
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• M Phase Cell Cycle Checkpoints (drug effects)
• Neoplasms
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Quinazolines (pharmacology)
• RNA Interference
• RNA, Small Interfering
• Survivin
• TNF-Related Apoptosis-Inducing Ligand (administration & dosage, metabolism, pharmacology)