Fassmannová Dominika, Sedlák František, Sedláček Jindřich, Špička Ivan, Grantz Šašková Klára
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, 16610 Prague, Czech Republic.
Department of Genetics and Microbiology, Charles University, Viničná 5, 12843 Prague, Czech Republic.
Cancers (Basel). 2020 Apr 25;12(5):1065. doi: 10.3390/cancers12051065.
Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the TCF11/Nrf1 transcription factor, which activates proteasome gene re-synthesis upon impairment of the proteasome function. Thus, inhibiting this recovery pathway potentiates the cytotoxic effect of proteasome inhibitors and could benefit treatment outcomes. DDI2 protease, the 3D structure of which resembles the HIV protease, serves as the key player in TCF11/Nrf1 activation. Previous work found that some HIV protease inhibitors block DDI2 in cell-based experiments. Nelfinavir, an oral anti-HIV drug, inhibits the proteasome and/or pAKT pathway and has shown promise for treatment of relapsed/refractory multiple myeloma. Here, we describe how nelfinavir inhibits the TCF11/Nrf1-driven recovery pathway by a dual mode of action. Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir's effectiveness in the treatment of multiple myeloma.
蛋白酶体抑制剂是多发性骨髓瘤治疗的支柱。然而，由于对该疗法产生耐药性，疾病会进展或早期复发。对蛋白酶体抑制产生耐药性的一个重要原因是所谓的反弹反应，这是一种由TCF11/Nrf1转录因子驱动的恢复途径，在蛋白酶体功能受损时激活蛋白酶体基因的重新合成。因此，抑制这种恢复途径可增强蛋白酶体抑制剂的细胞毒性作用，并可能改善治疗效果。DDI2蛋白酶的三维结构类似于HIV蛋白酶，是TCF11/Nrf1激活的关键因素。先前的研究发现，一些HIV蛋白酶抑制剂在基于细胞的实验中可阻断DDI2。奈非那韦是一种口服抗HIV药物，可抑制蛋白酶体和/或pAKT途径，并已显示出治疗复发/难治性多发性骨髓瘤的前景。在此，我们描述了奈非那韦如何通过双重作用模式抑制TCF11/Nrf1驱动的恢复途径。奈非那韦降低了TCF11/Nrf1的总蛋白水平，并抑制了TCF11/Nrf1的蛋白水解过程，可能是通过干扰DDI2蛋白酶，从而降低了细胞核中TCF11/Nrf1的蛋白水平。我们提出了一种总体机制来解释奈非那韦在治疗多发性骨髓瘤中的有效性。
