Understanding and targeting Nrf1-mediated proteasome recovery pathway in cancer

描述(申请人提供)：在哺乳动物细胞中抑制蛋白酶体导致蛋白酶体基因转录上调，从而为细胞提供维持蛋白酶体水平的内稳态控制机制。初步研究表明，这种反应是由转录因子Nrf1(也称为Nfe2l1)介导的，该因子的敲除使癌细胞对蛋白酶体抑制剂的治疗敏感。目前建议的总体目标是进一步了解这一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，特别是当与蛋白酶体抑制剂联合使用时。指导阶段的特定目标旨在了解蛋白酶体抑制后Nrf1激活的机制，并评估耗尽Nrf1在共价蛋白酶体抑制剂治疗小鼠异种移植瘤中的作用。在独立阶段的特定目的是为了了解p97/VCP及其辅助因子在Nrf1激活中的作用，并寻找Nrf1介导的蛋白酶体恢复途径的新的化学抑制剂。这项拟议的工作有可能阐明蛋白酶体恢复途径的功能，并为开发以泛素-蛋白酶体系统为靶点的新型抗癌疗法提供策略建议。 与公共卫生相关：最近，抑制蛋白质降解已成为对抗某些形式癌症的有效策略。这一建议旨在进一步了解细胞中蛋白质降解机制的诱导机制。这一知识有助于设计针对这种降解机制的新疗法，从而扩大可治疗的癌症类型的范围。

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.