Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells
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Susanne Lub1, Anke Maes1, Ken Maes1, Kim De Veirman1, Elke De Bruyne1, Eline Menu1, Karel Fostier1, Alboukadel Kassambara2,3, Jérôme Moreaux2,3,4, Dirk Hose5, Xavier Leleu6, Randall W. King7, Karin Vanderkerken1,*, Els Van Valckenborgh1,*
1Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
2Department of Biological Hematology, CHU Montpellier, Montpellier, France
3Institute of Human Genetics, CNRS-UPR1142, Montpellier, France
4University of Montpellier 1, UFR de Médecine, Montpellier, France
5Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany
6Service des maladies du sang, Hôpital Huriez, CHRU, Lille, France
7Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA
*These authors contributed equally to this work
Els Van Valckenborgh, e-mail: [email protected]
Keywords: multiple myeloma, high-risk, anaphase promoting complex/cyclosome, Cdc20, proTAME
Received: July 28, 2015 Accepted: November 26, 2015 Published: December 26, 2015
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.
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