The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma

• Published in: British journal of cancer 2019-06, Vol.120 (12), p.1137-1146
• Main Authors: Maes, Anke, Maes, Ken, De Raeve, Hendrik, De Smedt, Eva, Vlummens, Philip, Szablewski, Vanessa, Devin, Julie, Faict, Sylvia, De Veirman, Kim, Menu, Eline, Offner, Fritz, Spaargaren, Marcel, Moreaux, Jérôme, Vanderkerken, Karin, Van Valckenborgh, Els, De Bruyne, Elke
• Format: Article
• Language: English
• Subjects: 631/67/1990/291/1621/1915; 631/80/641/1655; Anaphase; Anaphase-promoting complex; Anaphase-Promoting Complex-Cyclosome - antagonists & inhibitors; Anaphase-Promoting Complex-Cyclosome - metabolism; Antigens, CD - biosynthesis; Antigens, CD - genetics; Apoptosis; Apoptosis - drug effects; B-cell lymphoma; Bcl-2 protein; Bcl-x protein; Biomedical and Life Sciences; Biomedicine; Cadherins - biosynthesis; Cadherins - genetics; Cancer Research; Caspase; Cdc20 Proteins - biosynthesis; Cdc20 Proteins - genetics; Cell Line, Tumor; Cyclin B1; Doxorubicin; Drug Resistance; E-cadherin; Epidemiology; Gene Expression Profiling; Humans; Immunohistochemistry; Inactivation; Life Sciences; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphoma, Mantle-Cell - drug therapy; Lymphoma, Mantle-Cell - metabolism; Lymphoma, Mantle-Cell - pathology; Mantle cell lymphoma; Metaphase; Mitosis; Molecular Medicine; Molecular Targeted Therapy; Oncology; Prodrugs - pharmacology; Prognosis; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tosylarginine Methyl Ester - pharmacology; Tumor Cells, Cultured
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-019-0471-0

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.