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.
Highlights
Multiple myeloma (MM) is a plasma cell cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM)
We assessed the distribution of Cdc20 expression in primary MM cells using three gene expression-based high-risk scores namely the RS, GPI and UAMS HRS scores [21,22,23]
In this study we investigated if the anaphase promoting complex/cyclosome (APC/C), and its co-activator Cdc20 could be a potential target in MM
Summary
Multiple myeloma (MM) is a plasma cell cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). A great improvement in the survival of MM patients was achieved the past decade due to the development of novel treatment options including novel agents and autologous stem cell transplantation (ASCT) for younger patients. These novel agents include the proteasome inhibitor bortezomib and the immunomodulatory drug lenalidomide. The ubiquitin-proteasome system (UPS) is highly regulated and controls different protein functions and processes such as proliferation, metabolism and apoptosis by targeting cellular proteins for degradation. There is an increasing interest in ubiquitin ligases as targets since they play a key role in the UPS by determining the protein to be ubiquitylated and thereby controlling cell function in a very specific way
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