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Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells.
- Source :
-
Oncotarget [Oncotarget] 2016 Jan 26; Vol. 7 (4), pp. 4062-76. - Publication Year :
- 2016
-
Abstract
- The anaphase promoting complex/cyclosome (APC/C) is an ubiquitin ligase involved in cell cycle. During the metaphase-anaphase transition the APC/C is activated by Cdc20. The aim of this study is to elucidate the importance and therapeutic potential of APC/C and its co-activator Cdc20 in multiple myeloma (MM). Gene expression analysis revealed that Cdc20 was expressed at higher levels in gene expression-based high-risk MM patients. Moreover, high Cdc20 expression correlated with poor prognosis. Treatment of human myeloma cell lines with proTAME, an APC/C inhibitor, resulted in an accumulation of APC/CCdc20 substrate cyclin B1 and an accumulation of cells in metaphase. Moreover we observed a significant dose-dependent decrease in viability and increase in apoptosis in MM cells upon proTAME treatment. The induction of apoptosis was accompanied with caspase 3, 8, 9 and PARP cleavage. A similar metaphase arrest and induction of apoptosis were obtained with specific knockdown of Cdc20. In addition, we demonstrated the accumulation of Bim was partially responsible for the observed cell death. Combining proTAME with another APC/C inhibitor apcin or the alkylating agent melphalan resulted in enhanced anti-MM activity. This study suggests that the APC/C and its co-activator Cdc20 could be a new and promising target especially in high-risk MM patients.
- Subjects :
- Antineoplastic Agents, Alkylating pharmacology
Blotting, Western
Cdc20 Proteins metabolism
Cell Proliferation drug effects
Gene Expression Profiling
Humans
Immunoenzyme Techniques
Multiple Myeloma drug therapy
Multiple Myeloma metabolism
Tumor Cells, Cultured
Anaphase-Promoting Complex-Cyclosome antagonists & inhibitors
Apoptosis drug effects
Carbamates pharmacology
Cell Cycle Checkpoints drug effects
Diamines pharmacology
Melphalan pharmacology
Mitosis drug effects
Multiple Myeloma pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26716651
- Full Text :
- https://doi.org/10.18632/oncotarget.6768