Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells

Susanne Lub, Anke Maes, Ken Maes, Kim De Veirman, Elke De Bruyne, Eline Menu, Karel Fostier, Alboukadel Kassambara, Jérôme Moreaux, D. Hose, Xavier Leleu, Randall W King, Karin Vanderkerken, Els Van Valckenborgh

Onderzoeksoutput: Articlepeer review

33 Citaten (Scopus)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)4062-4076
Aantal pagina's15
TijdschriftOncotarget
Volume7
Nummer van het tijdschrift4
DOI's
StatusPublished - 26 jan 2016

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