The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition
The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition
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DOI：
10.1182/blood-2008-08-172734
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发表时间：
2009-03-26
期刊：
影响因子：
20.3
通讯作者：
Cenci, Simone
中科院分区：
文献类型：
--
作者：
Bianchi, Giada;Oliva, Laura;Cenci, Simone
蛋白酶体抑制剂（PI）对多发性骨髓瘤（MM）有效，但其作用机制和个体易感性的基础尚不清楚。最近的工作将PI敏感性与蛋白质合成和蛋白酶体活性联系起来，提出了不同水平的蛋白酶体表达和工作量是否是MM细胞（MMC）中PI敏感性的基础的问题。利用人MM线的特点是差分PI敏感性，我们报告说，高度敏感的MMC表达较低的蛋白酶体水平和较高的蛋白酶体的工作量比相对PI耐药的MMC，导致在积累的多聚泛素化的蛋白质的代价游离泛素（蛋白酶体应激）。操纵蛋白酶体表达或工作量改变PI的凋亡敏感性，表明蛋白酶体应激和MMC凋亡反应之间的因果关系。原发性患者源性MMC的细胞内免疫染色显示，多泛素化蛋白标志着肿瘤性浆细胞，与患者内和患者间的免疫球蛋白（IG）含量呈正相关。此外，初级MMC的总体蛋白酶体活性与PI的凋亡敏感性呈负相关。总之，我们的数据表明，蛋白酶体工作量和降解能力之间的平衡代表了MMCs对PI的凋亡敏感性的关键决定因素，可能为识别反应性指标和设计新型联合治疗提供了框架。（血。2009; 113：3040-3049）
Proteasome inhibitors (PIs) are effective against multiple myeloma (MM), but the mechanisms of action and bases of individual susceptibility remain unclear. Recent work linked PI sensitivity to protein synthesis and proteasome activity, raising the question whether different levels of proteasome expression and workload underlie PI sensitivity in MM cells (MMCs). Exploiting human MM lines characterized by differential PI sensitivity, we report that highly sensitive MMCs express lower proteasome levels and higher proteasomal workload than relatively PI-resistant MMCs, resulting in the accumulation of polyubiquitinated proteins at the expense of free ubiquitin (proteasome stress). Manipulating proteasome expression or workload alters apoptotic sensitivity to PI, demonstrating a cause-effect relationship between proteasome stress and apoptotic responses in MMCs. Intracellular immunostaining in primary, patient-derived MMCs reveals that polyubiquitinated proteins hallmark neoplastic plasma cells, in positive correlation with immuno-globulin (Ig) content, both intra-and interpatient. Moreover, overall proteasome activity of primary MMCs inversely correlates with apoptotic sensitivity to PI. Altogether, our data indicate that the balance between proteasome workload and degradative capacity represents a critical determinant of apoptotic sensitivity of MMCs to PI, potentially providing a framework for identifying indicators of responsiveness and designing novel combination therapies. (Blood. 2009; 113: 3040-3049)