Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells.
Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells.
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DOI：
10.18632/oncotarget.14405
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发表时间：
2017-02-21
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影响因子：
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通讯作者：
Hernandez-Ilizaliturri FJ
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作者：
Gu JJ;Kaufman GP;Mavis C;Czuczman MS;Hernandez-Ilizaliturri FJ
泛素-蛋白酶体系统（UPS）在利妥昔单抗化疗耐药中发挥作用，硼替佐米（BTZ）具有caspase依赖性（即Bak稳定化）和较少表征的caspase非依赖性作用机制。在这里，我们定义了btz诱导的不依赖于caspase的细胞死亡途径。一组利妥昔单抗敏感（RSCL），利妥昔单抗耐药细胞系（RRCL）和来自淋巴瘤患者的原发肿瘤细胞（N = 13）暴露于BTZ。定量测定细胞活力、细胞周期、衰老和有丝分裂指数的变化。在静息状态下，RRCL表现为低增殖率、s期细胞积累和衰老。RRCL暴露于BTZ可减少细胞衰老，诱导G2-M期细胞周期停滞，并与有丝分裂灾难有关。BTZ稳定了RRCL和原发肿瘤细胞中的p21、CDC2和细胞周期蛋白B。短暂p21敲低可减轻btz诱导的衰老抑制、G2-M细胞周期阻滞和有丝分裂灾难。我们的数据表明BTZ可以诱导细胞凋亡或有丝分裂突变，p21在BTZ抗RRCL活性中起关键作用。
The ubiqutin-proteasome system (UPS) plays a role in rituximab-chemotherapy resistance and bortezomib (BTZ) possesses caspase-dependent (i.e. Bak stabilization) and a less characterized caspase–independent mechanism-of-action(s). Here, we define BTZ-induced caspase-independent cell death pathways. A panel of rituximab-sensitive (RSCL), rituximab-resistant cell lines (RRCL) and primary tumor cells derived from lymphoma patients (N = 13) were exposed to BTZ. Changes in cell viability, cell-cycle, senescence, and mitotic index were quantified. In resting conditions, RRCL exhibits a low-proliferation rate, accumulation of cells in S-phase and senescence. Exposure of RRCL to BTZ reduces cell senescence, induced G2-M phase cell-cycle arrest, and is associated with mitotic catastrophe. BTZ stabilized p21, CDC2, and cyclin B in RRCL and in primary tumor cells. Transient p21 knockdown alleviates BTZ-induced senescence inhibition, G2-M cell cycle blockade, and mitotic catastrophe. Our data suggest that BTZ can induce apoptosis or mitotic catastrophe and that p21 has a pivotal role in BTZ activity against RRCL.