Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
Biomolecules. 2020 Mar 26;10(4):501. doi: 10.3390/biom10040501.
Currently proteasome inhibitors bortezomib, carfilzomib, and ixazomib are successfully used in clinics to treat multiple myeloma. However, these agents show limited efficacy against solid tumors. Identification of drugs that can potentiate the action of proteasome inhibitors could help expand the use of this therapeutic modality to solid tumors. Here, we found that bromodomain extra-terminal (BET) family protein inhibitors such as JQ1, I-BET762, and I-BET151 synergize with carfilzomib in multiple solid tumor cell lines. Mechanistically, BET inhibitors attenuated the ability of the transcription factor Nrf1 to induce proteasome genes in response to proteasome inhibition, thus, impeding the bounce-back response of proteasome activity, a critical pathway by which cells cope with proteotoxic stress. Moreover, we found that treatment with BET inhibitors or depletion of Nrf1 exacerbated the unfolded protein response (UPR), signaling that was initiated by proteasome inhibition. Taken together, our work provides a mechanistic explanation behind the synergy between proteasome and BET inhibitors in cancer cell lines and could prompt future preclinical and clinical studies aimed at further investigating this combination.
目前蛋白酶体抑制剂硼替佐米、卡非佐米和伊沙佐米已成功用于治疗多发性骨髓瘤。然而，这些药物对实体瘤的疗效有限。鉴定能增强蛋白酶体抑制剂作用的药物可能有助于将这种治疗模式扩展到实体瘤。在这里，我们发现溴结构域末端（BET）家族蛋白抑制剂，如 JQ1、I-BET762 和 I-BET151，与卡非佐米在多种实体肿瘤细胞系中具有协同作用。从机制上讲，BET 抑制剂减弱了转录因子 Nrf1 在蛋白酶体抑制时诱导蛋白酶体基因的能力，从而阻碍了蛋白酶体活性的反弹反应，这是细胞应对蛋白毒性应激的关键途径。此外，我们发现 BET 抑制剂的治疗或 Nrf1 的耗竭加剧了未折叠蛋白反应（UPR），这是由蛋白酶体抑制引发的信号。总之，我们的工作为蛋白酶体和 BET 抑制剂在癌细胞系中的协同作用提供了一种机制解释，并可能促使未来进行旨在进一步研究这种组合的临床前和临床研究。
