Understanding and targeting Nrf1-mediated proteasome recovery pathway in cancer

项目摘要/摘要 哺乳动物细胞中蛋白酶体的抑制导致转录 上调蛋白酶体基因，从而为细胞提供动态平衡 维持蛋白酶体水平的控制机制。初步研究表明 这种反应是由转录因子Nrf1(也称为 NFe2L1)和该因子敲除使癌细胞对蛋白酶体敏感 抑制剂治疗。目前提案的总体目标是进一步 了解这种蛋白酶体稳态途径背后的机制，并 评估抑制这一途径是否可以成为体内可行的抗癌策略， 尤其是与蛋白酶体抑制剂联合使用时。具体目标 在指导阶段，旨在了解Nrf1的机制 蛋白酶体抑制后的激活和评估耗竭的效用 Nrf1共价蛋白酶体治疗小鼠移植瘤的实验研究 抑制剂。独立阶段的具体目标旨在 了解p97/VCP及其辅助因子在Nrf1激活中的作用 鉴定新的Nrf1介导的蛋白酶体恢复的化学抑制剂 路径。这项拟议的工作有可能阐明 蛋白酶体恢复途径，并提出了应对策略。 以泛素为靶点的新型抗癌治疗药物的开发 蛋白酶体系统。

Project Summary/Abstract Proteasome inhibition in mammalian cells results in transcriptional upregulation of proteasome genes, thereby providing the cell with a homeostatic control mechanism to maintain proteasome levels. Preliminary studies indicated that this response was mediated by the transcription factor Nrf1 (also called Nfe2l1) and that knockdown of this factor sensitized cancer cells to proteasome inhibitor treatments. The overall goal of the current proposal is to further understand the mechanism behind this proteasome homeostatic pathway and to evaluate if inhibition of this pathway could be a viable anti-cancer strategy in vivo, especially when used in conjunction with proteasome inhibitors. Specific Aims during the mentored phase are designed to understand the mechanism of Nrf1 activation following proteasome inhibition and to evaluate the utility of depleting Nrf1 in the treatment of mouse xenograft tumors with covalent proteasome inhibitors. Specific Aims during the independent phase are designed to understand the role of p97/VCP and its co-factors in Nrf1 activation and to identify novel chemical inhibitors of the Nrf1-mediated proteasome recovery pathway. The proposed work has the potential to shed light on the functioning of the proteasome recovery pathway and also suggest strategies for the development of novel anti-cancer therapeutics that target the ubiquitin- proteasome system.