Understanding and targeting Nrf1-mediated proteasome recovery pathway in cancer

描述（由申请人提供）：哺乳动物细胞中的蛋白酶体抑制导致蛋白酶体基因的转录上调，从而为细胞提供维持蛋白酶体水平的稳态控制机制。初步研究表明，这种反应是由转录因子Nrf1（也称为Nfe2l1）介导的，该因子的敲低使癌细胞对蛋白酶体抑制剂治疗敏感。当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，并评估这种途径的抑制是否可能是一种可行的体内抗癌策略，特别是当与蛋白酶体抑制剂联合使用时。在指导阶段的特定目的旨在了解蛋白酶体抑制后Nrf1激活的机制，并评估使用共价蛋白酶体抑制剂消耗Nrf1治疗小鼠异种移植肿瘤的效用。独立阶段的特异性目的旨在了解p97/VCP及其辅助因子在Nrf1激活中的作用，并鉴定Nrf1介导的蛋白酶体恢复途径的新型化学抑制剂。所提出的工作有可能阐明蛋白酶体恢复途径的功能，并为开发针对泛素-蛋白酶体系统的新型抗癌疗法提供策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Inhibition of protein degradation has recently emerged as an effective strategy against some forms of cancer. This proposal aims to further understand the mechanism by which the protein degradation machinery in the cells is induced. This knowledge can be useful in devising novel therapeutics that target this degradation machinery thereby expanding the repertoire of cancer types that can be treated.