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有丝分裂灾难和细胞周期停滞是硼替佐米在利妥昔单抗耐药的B细胞淋巴瘤细胞中执行的替代性细胞死亡途径。

Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells.

作者信息

Gu Juan J, Kaufman Gregory P, Mavis Cory, Czuczman Myron S, Hernandez-Ilizaliturri Francisco J

机构信息

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.

出版信息

Oncotarget. 2017 Feb 21;8(8):12741-12753. doi: 10.18632/oncotarget.14405.

DOI:10.18632/oncotarget.14405
PMID:28055975
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5355050/
Abstract

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.

摘要

泛素-蛋白酶体系统（UPS）在利妥昔单抗化疗耐药中起作用，而硼替佐米（BTZ）具有半胱天冬酶依赖性（即Bak稳定化）和一种特征较少的半胱天冬酶非依赖性作用机制。在此，我们定义了BTZ诱导的半胱天冬酶非依赖性细胞死亡途径。将一组利妥昔单抗敏感（RSCL）、利妥昔单抗耐药细胞系（RRCL）以及源自淋巴瘤患者的原代肿瘤细胞（N = 13）暴露于BTZ。对细胞活力、细胞周期、衰老和有丝分裂指数的变化进行了定量分析。在静息状态下，RRCL表现出低增殖率、细胞在S期积累和衰老。RRCL暴露于BTZ可减少细胞衰老，诱导G2-M期细胞周期阻滞，并与有丝分裂灾难相关。BTZ使RRCL和原代肿瘤细胞中的p21、CDC2和细胞周期蛋白B稳定。短暂敲低p21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可诱导凋亡或有丝分裂灾难，且p21在BTZ针对RRCL的活性中起关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/5e78b04229d7/oncotarget-08-12741-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/9144ef46519f/oncotarget-08-12741-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/d6419d49afcf/oncotarget-08-12741-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/d73377d2f619/oncotarget-08-12741-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/224ea39b274f/oncotarget-08-12741-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/1ea840a81e5f/oncotarget-08-12741-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/5e78b04229d7/oncotarget-08-12741-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/9144ef46519f/oncotarget-08-12741-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/d6419d49afcf/oncotarget-08-12741-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/d73377d2f619/oncotarget-08-12741-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/224ea39b274f/oncotarget-08-12741-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/1ea840a81e5f/oncotarget-08-12741-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5ce9/5355050/5e78b04229d7/oncotarget-08-12741-g006.jpg

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