后期促进复合物/周期素体：弥漫性大 B 细胞淋巴瘤和套细胞淋巴瘤的一个新的有前途的靶点。
The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma.
机构信息
Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
Department of Pathology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
出版信息
Br J Cancer. 2019 Jun;120(12):1137-1146. doi: 10.1038/s41416-019-0471-0. Epub 2019 May 15.
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.
背景
侵袭性 B 细胞非霍奇金淋巴瘤弥漫性大 B 细胞淋巴瘤（DLBCL）和套细胞淋巴瘤（MCL）的特点是增殖率高。后期促进复合物/细胞周期蛋白（APC/C）及其共激活因子 Cdc20 和 Cdh1 代表有丝分裂中的一个重要检查点。在这里，研究了 APC/C 及其共激活因子在 DLBCL 和 MCL 中的作用。
方法
使用 GEP 数据和免疫组织化学研究了 Cdc20 和 Cdh1 的表达及其预后价值。此外，还使用小分子抑制剂 proTAME 评估了 APC/C 靶向的治疗潜力，并通过 Western blot 研究了其作用机制。
结果
我们证明 Cdc20 在 DLBCL 和侵袭性 MCL 中高度表达，与 DLBCL 的预后不良相关。ProTAME 诱导中期延长，导致 APC/C-Cdc20 底物细胞周期蛋白 B1 的积累、Bcl-2 和 Bcl-xL 的失活/降解以及 caspase 依赖性凋亡。此外，proTAME 还显著增强了临床相关药物阿霉素和 venetoclax 的抗淋巴瘤作用。
结论
我们首次将 APC/C 确定为 DLBCL 和 MCL 的一个新的有前途的靶点。此外，我们提供的证据表明，Cdc20 可能是 DLBCL 和 MCL 中的一个新的独立预后因素。
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