Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress
Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress
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DOI：
10.1038/leu.2010.137
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发表时间：
2010-08-01
期刊：
影响因子：
11.4
通讯作者：
Ueda, R.
中科院分区：
文献类型：
--
作者：
Ri, M.;Iida, S.;Ueda, R.
硼替佐米是治疗多发性骨髓瘤（MM）的有效药物。为了研究与获得性耐药相关的潜在机制，我们建立了两个硼替佐米耐药MM细胞系，KMS-11/BTZ和OPM-2/BTZ，其50%抑制浓度值分别是其亲本细胞系的24.7倍和16.6倍。暴露于药物后，在硼替佐米耐药细胞中未观察到半胱天冬酶和仅BH 3蛋白如Noxa的活化。与亲代细胞相比，硼替佐米耐药细胞中多聚泛素化蛋白的积累减少，这与通过下调CHOP表达评估的灾难性ER应激的避免有关。这些耐药MM细胞在编码蛋白酶体β 5亚基（PSMB 5）的基因中具有独特的点突变G322 A，可能导致该亚基的硼替佐米结合口袋的构象变化。与表达野生型PSMB 5或亲本细胞相比，转染表达突变PSMB 5的KMS-11亲本细胞也显示硼替佐米诱导的细胞凋亡减少。突变的PSMB 5的表达与未折叠蛋白的积累的预防有关。因此，一部分MM细胞可能通过抑制未折叠蛋白积累和随后的过度ER应激（PSMB 5基因突变）来抑制凋亡信号，从而获得硼替佐米抗性。Leukemia（2010）24，1506-1512; doi：10.1038/leu.2010.137; 2010年6月17日在线发表
Bortezomib is an effective agent for treating multiple myeloma (MM). To investigate the underlying mechanisms associated with acquired resistance to this agent, we established two bortezomib-resistant MM cell lines, KMS-11/BTZ and OPM-2/BTZ, the 50% inhibitory concentration values of which were respectively 24.7- and 16.6-fold higher than their parental cell lines. No activation of caspase and BH3-only proteins such as Noxa was noted in bortezomib-resistant cells after exposure to the drug. The accumulation of polyubiquitinated proteins was reduced in bortezomib-resistant cells compared with the parental cells, associated with avoidance of catastrophic ER stress as assessed by downregulation of CHOP expression. These resistant MM cells have a unique point mutation, G322A, in the gene encoding the proteasome beta 5 subunit (PSMB5), likely resulting in conformational changes to the bortezomib-binding pocket of this subunit. KMS-11 parental cells transfected to express mutated PSMB5 also showed reduced bortezomib-induced apoptosis compared with those expressing wild-type PSMB5 or the parental cells. Expression of mutated PSMB5 was associated with the prevention of the accumulation of unfolded proteins. Thus, a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the PSMB5 gene. Leukemia (2010) 24, 1506-1512; doi:10.1038/leu.2010.137;published online 17 June 2010