Abstract
BackgroundThe aggressive B-cell non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are characterised by a high proliferation rate. The anaphase-promoting complex/cyclosome (APC/C) and its co-activators Cdc20 and Cdh1 represent an important checkpoint in mitosis. Here, the role of the APC/C and its co-activators is examined in DLBCL and MCL.MethodsThe expression and prognostic value of Cdc20 and Cdh1 was investigated using GEP data and immunohistochemistry. Moreover, the therapeutic potential of APC/C targeting was evaluated using the small-molecule inhibitor proTAME and the underlying mechanisms of action were investigated by western blot.ResultsWe demonstrated that Cdc20 is highly expressed in DLBCL and aggressive MCL, correlating with a poor prognosis in DLBCL. ProTAME induced a prolonged metaphase, resulting in accumulation of the APC/C-Cdc20 substrate cyclin B1, inactivation/degradation of Bcl-2 and Bcl-xL and caspase-dependent apoptosis. In addition, proTAME strongly enhanced the anti-lymphoma effect of the clinically relevant agents doxorubicin and venetoclax.ConclusionWe identified for the first time APC/C as a new, promising target in DLBCL and MCL. Moreover, we provide evidence that Cdc20 might be a novel, independent prognostic factor in DLBCL and MCL.
Highlights
The aggressive B-cell non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are characterised by a high proliferation rate
The aim of this study is to investigate the expression of the anaphase-promoting complex/cyclosome (APC/C) co-activators Cdc[20] and Cdh[1] and the therapeutic potential of APC/C targeting in DLBCL and MCL
Cdc[20] expression is increased in DLBCL and MCL patients and associated with poor survival To investigate the clinical relevance of the APC/C in the aggressive B-cell malignancies DLBCL and MCL, the gene expression levels of the two APC/C co-activators, namely Cdc[20] and Cdh[1], were analysed using publicly available gene expression profiling (GEP) datasets
Summary
The aggressive B-cell non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are characterised by a high proliferation rate. The clinical use of cell cycle targeting agents, such as the microtubule-targeting agent vincristine, has proven that this is an interesting approach in the treatment of high-grade B-cell NHL.[4] These agents induce severe toxicity and are associated with multidrug resistance development.[5] Clinical studies are currently ongoing to find more selective cell cycle targets by blocking either the interphase (e.g. Cdk inhibitors) or mitotic entry (e.g. microtubule-targeting agents, Plk-1 and aurora kinase inhibitors).[6] In B-cell NHL, the anti-lymphoma effects of these agents were either disappointing or the trials were suspended early due to toxicity issues.[6,7,8,9] Recent preclinical studies show that targeting molecules involved in the mitotic exit, such as the anaphase-promoting complex/cyclosome (APC/C), is a better strategy since it provokes a more permanent mitotic arrest, thereby reducing the chance of mitotic slippage and enhancing mitotic cell death.[10] The activation of the APC/C, an
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