Evidence of a Role for Activation of Wnt/β-Catenin Signaling in the Resistance of Plasma Cells to Lenalidomide
Evidence of a Role for Activation of Wnt/β-Catenin Signaling in the Resistance of Plasma Cells to Lenalidomide
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DOI：
10.1074/jbc.m110.180208
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发表时间：
2011-04-01
影响因子：
4.8
通讯作者：
Orlowski, Robert Z.
中科院分区：
文献类型：
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作者：
Bjorklund, Chad C.;Ma, Wencai;Orlowski, Robert Z.
来那度胺在我们针对多发性骨髓瘤的化疗药物中起着重要作用，部分是通过发挥直接的抗增殖和促凋亡作用。不幸的是，长期暴露导致通过未知机制产生耐药性，因此我们试图确定可能导致这种表型的途径。慢性药物暴露产生的骨髓瘤细胞系耐受来那度胺的直接作用，耐药性高达2,500倍。基因表达谱分析和途径分析鉴定了Wnt/β-连环蛋白途径的失调，这是四个独立细胞分离株和一对原代浆细胞样品的一致变化。急性药物治疗也使β-连环蛋白转录增加3倍或更多，急性和慢性暴露均导致β-连环蛋白积累增加20倍或更多。这产生了Wnt/β-连环蛋白途径激活，如通过淋巴增强因子/T细胞因子启动子报告子的活性增加所判断的，并且增强了下游靶细胞周期蛋白D1和c-Myc的积累。β-连环蛋白破坏复合物的组分也受到来那度胺的影响，来那度胺抑制酪蛋白激酶1 α表达，同时增加糖原合成酶激酶3 α/β磷酸化。用重组Wnt-3a刺激Wnt/β-连环蛋白信号传导，或通过β-连环蛋白的过表达，降低来那度胺的抗增殖活性。相反，用小发夹RNA抑制β-连环蛋白恢复了浆细胞对来那度胺的敏感性。总之，这些发现支持了来那度胺介导浆细胞中Wnt/β-连环蛋白信号传导的激活作为通过转录和翻译后水平的作用诱导化学抗性的机制的假设。
Lenalidomide plays an important role in our chemotherapeutic armamentarium against multiple myeloma, in part by exerting direct anti-proliferative and pro-apoptotic effects. Unfortunately, long-term exposure leads to the development of drug resistance through unknown mechanisms, and we therefore sought to identify pathways that could be responsible for this phenotype. Chronic drug exposure produced myeloma cell lines that were tolerant of the direct effects of lenalidomide, with a degree of resistance of up to 2,500-fold. Gene expression profiling and pathway analysis identified dysregulation of the Wnt/beta-catenin pathway as a consistent change across four independent cell isolates, and a pair of primary plasma cell samples. Acute drug treatment also increased beta-catenin transcription by 3-fold or more, and both acute and chronic exposure resulted in enhanced accumulation of beta-catenin protein by up to 20-fold or more. This produced Wnt/beta-catenin pathway activation, as judged by increased activity of a lymphoid enhancer factor/T-cell factor promoter reporter, and enhanced accumulation of the downstream targets cyclin D1 and c-Myc. Components of the beta-catenin destruction complex were also impacted by lenalidomide, which suppressed casein kinase 1 alpha expression while augmenting glycogen synthase kinase 3 alpha/beta phosphorylation. Stimulation of Wnt/beta-catenin signaling with recombinant Wnt-3a, or by overexpression of beta-catenin, reduced the anti-proliferative activity of lenalidomide. Conversely, suppression of beta-catenin with small hairpin RNAs restored plasma cell sensitivity to lenalidomide. Together, these findings support the hypothesis that lenalidomide mediates activation of Wnt/beta-catenin signaling in plasma cells as a mechanism of inducible chemoresistance through effects at the transcriptional and post-translational levels.