title: Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells.
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.
authors.affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lub
authors.affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Anke
authors.initials: A
authors.lastname: Maes
authors.affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ken
authors.initials: K
authors.lastname: Maes
authors.affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: De Veirman
authors.affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Elke
authors.initials: E
authors.lastname: De Bruyne
authors.affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
authors.affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Fostier
authors.affiliation: Department of Biological Hematology, CHU Montpellier, Montpellier, France.|Institute of Human Genetics, CNRS-UPR1142, Montpellier, France.
authors.forename: Alboukadel
authors.initials: A
authors.lastname: Kassambara
authors.affiliation: Department of Biological Hematology, CHU Montpellier, Montpellier, France.|Institute of Human Genetics, CNRS-UPR1142, Montpellier, France.|University of Montpellier 1, UFR de Médecine, Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Moreaux
authors.affiliation: Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hose
authors.affiliation: Service des maladies du sang, Hôpital Huriez, CHRU, Lille, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Randall W
authors.initials: RW
authors.lastname: King
authors.affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Van Valckenborgh
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000037:antagonists & inhibitors*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002219:Carbamates / Q000494:pharmacology*; D064199:Cdc20 Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003959:Diamines / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008558:Melphalan / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002219:Carbamates; D064199:Cdc20 Proteins; D003959:Diamines; C000593255:apcin; C577488:CDC20 protein, human; D064173:Anaphase-Promoting Complex-Cyclosome; D008558:Melphalan
keywords: Cdc20; anaphase promoting complex/cyclosome; high-risk; multiple myeloma; proTAME