Bortezomib modulates surface CD20 in B-cell malignancies and affects rituximab-mediated complement-dependent cytotoxicity
Bortezomib modulates surface CD20 in B-cell malignancies and affects rituximab-mediated complement-dependent cytotoxicity
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DOI：
10.1182/blood-2009-09-244129
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发表时间：
2010-05-06
期刊：
影响因子：
20.3
通讯作者：
Golab, Jakub
中科院分区：
文献类型：
--
作者：
Bil, Jacek;Winiarska, Magdalena;Golab, Jakub
在许多患者中，对利妥昔单抗治疗无反应，促使阐明潜在的分子途径。最近观察到，对利妥昔单抗耐药的淋巴瘤细胞表现出泛素-蛋白酶体系统(UPS)成分的上调。因此，我们更详细地研究了该系统在调节CD20水平中的作用以及蛋白酶体抑制剂对利妥昔单抗介导的补体依赖性细胞毒作用(R-CDC)的影响。我们观察到Raji细胞与利妥昔单抗孵育会导致泛素化CD20水平增加。然而，抑制UPS与上调表面CD20水平无关，尽管它显著增加了其泛素化。Raji细胞与10或20 nm硼替佐米短期(24小时)孵育不改变表面CD20水平，但使CD20(+)淋巴瘤细胞对R-CDC增敏。与20 nm Bortezomib共同孵育48小时，或与50 nm Bortezomib共同孵育24小时，细胞表面CD20水平和R-CDC均显著降低。这些作用可被蛋白质降解的溶酶体/自噬小体途径的抑制剂巴非霉素A1部分逆转。这些研究表明，CD20水平受两种蛋白分解系统的调节，蛋白酶体抑制剂的使用可能与R-CDC的意外负面影响有关。(血。2010；115(18)：3745-3755)
Unresponsiveness to rituximab treatment develops in many patients prompting elucidation of underlying molecular pathways. It was recently observed that rituximab-resistant lymphoma cells exhibit up-regulation of components of the ubiquitin-proteasome system (UPS). Therefore, we investigated in more detail the role of this system in the regulation of CD20 levels and the influence of proteasome inhibitors on rituximab-mediated complement-dependent cytotoxicity (R-CDC). We observed that incubation of Raji cells with rituximab leads to increased levels of ubiquitinated CD20. However, inhibition of the UPS was not associated with up-regulation of surface CD20 levels, although it significantly increased its ubiquitination. Short-term (24 hours) incubation of Raji cells with 10 or 20nM bortezomib did not change surface CD20 levels, but sensitized CD20(+) lymphoma cells to R-CDC. Prolonged (48 hours) incubation with 20nM bortezomib, or incubation with 50nM bortezomib for 24 hours led to a significant decrease in surface CD20 levels as well as R-CDC. These effects were partly reversed by bafilomycin A1, an inhibitor of lysosomal/autophagosomal pathway of protein degradation. These studies indicate that CD20 levels are regulated by 2 proteolytic systems and that the use of proteasome inhibitors may be associated with unexpected negative influence on R-CDC. (Blood. 2010; 115(18):3745-3755)