HSP70 inhibition by the small-molecule 2-phenylethynesulfonamide impairs protein clearance pathways in tumor cells.
HSP70 inhibition by the small-molecule 2-phenylethynesulfonamide impairs protein clearance pathways in tumor cells.
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DOI：
10.1158/1541-7786.mcr-11-0019
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
George DL
中科院分区：
文献类型：
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作者：
Leu JI;Pimkina J;Pandey P;Murphy ME;George DL
进化上保守的应激诱导的HSP70分子伴侣在维持蛋白质质量控制以应对各种形式的应激中起着核心作用。结构性升高的HSP70表达是许多肿瘤细胞的一个特征，并有助于它们的生存。我们最近发现小分子2-苯乙基磺酰胺(PES)是一种新型的HSP70抑制剂。在这里，我们提出证据表明，PES介导的对肿瘤细胞中HSP70家族蛋白的抑制会导致两个主要的蛋白质降解系统，即自噬-溶酶体系统和蛋白酶体途径的损害。HSP70家族蛋白与HSP90分子伴侣密切合作，维持其众多客户蛋白的稳定性和活性，PES导致HSP70/HSP90分子伴侣系统的破坏。结果，许多细胞蛋白，包括已知的HSP70/HSP90底物，在洗涤剂不溶的细胞部分中积累，表明聚集和功能失活。总体而言，PES同时扰乱了几个癌症关键的生存途径，支持了将HSP70作为癌症治疗的潜在方法的想法。
The evolutionarily conserved stress-inducible HSP70 molecular chaperone plays a central role in maintaining protein quality control in response to various forms of stress. Constitutively elevated HSP70 expression is a characteristic of many tumor cells and contributes to their survival. We recently identified the small-molecule 2-phenylethyenesulfonamide (PES) as a novel HSP70 inhibitor. Here we present evidence that PES-mediated inhibition of HSP70-family proteins in tumor cells results in an impairment of the two major protein degradation systems, namely the autophagy-lysosome system as well as the proteasome pathway. HSP70-family proteins work closely with the HSP90 molecular chaperone to maintain the stability and activities of their many client proteins and PES causes a disruption in the HSP70/HSP90 chaperone system. As a consequence, many cellular proteins, including known HSP70/HSP90 substrates, accumulate in detergent-insoluble cell fractions, indicative of aggregation and functional inactivation. Overall, PES simultaneously disrupts several cancer-critical survival pathways, supporting the idea of targeting HSP70 as a potential approach for cancer therapeutics.