The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma.
Anaphase-Promoting Complex-Cyclosome
/ antagonists & inhibitors
Antigens, CD
/ biosynthesis
Apoptosis
/ drug effects
Cadherins
/ biosynthesis
Cdc20 Proteins
/ biosynthesis
Cell Line, Tumor
Gene Expression Profiling
Humans
Immunohistochemistry
Lymphoma, Large B-Cell, Diffuse
/ drug therapy
Lymphoma, Mantle-Cell
/ drug therapy
Molecular Targeted Therapy
Prodrugs
/ pharmacology
Prognosis
RNA, Messenger
/ biosynthesis
Tosylarginine Methyl Ester
/ pharmacology
Tumor Cells, Cultured
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
07
09
2018
accepted:
17
04
2019
revised:
16
04
2019
pubmed:
16
5
2019
medline:
19
3
2020
entrez:
16
5
2019
Statut:
ppublish
Résumé
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 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. The 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. We 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. We 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.
Sections du résumé
BACKGROUND
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 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.
METHODS
The 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.
RESULTS
We 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.
CONCLUSION
We 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.
Identifiants
pubmed: 31089208
doi: 10.1038/s41416-019-0471-0
pii: 10.1038/s41416-019-0471-0
pmc: PMC6738099
doi:
Substances chimiques
Antigens, CD
0
CDH1 protein, human
0
Cadherins
0
Cdc20 Proteins
0
Prodrugs
0
RNA, Messenger
0
CDC20 protein, human
156288-95-8
Tosylarginine Methyl Ester
901-47-3
Anaphase-Promoting Complex-Cyclosome
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1137-1146Références
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