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首页> 外文期刊>Biochemical and Biophysical Research Communications >Designing an effective drug combination for ER stress loading in cancer therapy using a real-time monitoring system
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Designing an effective drug combination for ER stress loading in cancer therapy using a real-time monitoring system

机译：使用实时监测系统设计癌症治疗中ER应激载荷的有效药物组合

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Excess stress caused by accumulation of misfolded proteins inside the endoplasmic reticulum (ER) lumen can cause cells to undergo apoptosis. Misfolded proteins exported from ER to cytoplasm are ubiquitinated and mostly degraded by the proteasome, but can also be destroyed by autophagy mediated by the docking proteins p62 and NBRI. When misfolded proteins accumulate beyond the capacity of these clearance systems, they are transported to the microtubule organization center to form aggresomes, which are also degraded by autophagy. Together, these phenomena suggest the existence of a coordinated intracellular network for coping with the accumulation of misfolded proteins. Thus, rational inhibition of this network system might enhance killing of cancer cells subjected to pronounced ER stress loading. Based on this rationale, we sought to establish a quantitative assay for monitoring ER stress loading. MDA-MB231 cells stably transfected with the ERAI-Venus vector exhibited a strong XBPI splicing signal in response to ER stress. Using the IncuCyte cell imaging system, we monitored the fluorescence intensity of XBP1-Venus, normalized against cell density, as an ER stress indicator. This parameter correlated closely with other reporters of unfolded protein responses. Assessment of the XBP1-Venus signal during exposure to various drug combinations revealed that simultaneous inhibition of the proteasome, autophagy, and aggresome formation led to more effective ER stress loading and higher cytotoxicity than inhibition of only two components. Our data suggest that this monitoring system is a useful tool for designing effective drug combinations for ER stress loading in cancer therapy. (C) 2018 The Authors. Published by Elsevier Inc.
机译：由内质网（ER）内部（ER）内部的错误折叠蛋白质的积累引起的过量应激会导致细胞进行细胞凋亡。从er到细胞质出口的错误折叠蛋白质是泛素化的，并且由蛋白酶体大部分降低，但也可以通过对接蛋白P62和NBRI介导的自噬破坏。当错误折叠的蛋白质积聚超过这些间隙系统的容量时，它们被运输到微管组织中心以形成胚胎，其也通过自噬降解。这些现象表明，存在协调细胞内网络，用于应对错误折叠蛋白质的积累。因此，对该网络系统的合理抑制可能增强对经受显着ER应激载荷进行癌细胞的杀伤。基于该理由，我们试图建立用于监测ER应激载荷的定量测定。用Erai-Venus载体稳定地转染的MDA-MB231细胞表现出强烈的XBPI剪接信号，响应于ER应力。使用切割细胞成像系统，我们监测XbP1-venus的荧光强度，归一化抗细胞密度，作为ER应激指示器。该参数与展开蛋白质反应的其他记者密切相关。在暴露于各种药物组合期间对XBP1-venus信号的评估显示，同时抑制蛋白酶体，自噬和蛋白酶体的抑制导致更有效的ER应激载荷和更高的细胞毒性，而不是仅抑制两种组分。我们的数据表明，该监测系统是用于设计癌症治疗中ER应激载荷的有效药物组合的有用工具。 （c）2018作者。 elsevier公司发布

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