College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China; Department of Haematology, Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China.
Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
J Biol Chem. 2023 Jan;299(1):102798. doi: 10.1016/j.jbc.2022.102798. Epub 2022 Dec 14.
Chemotherapy resistance is the dominant challenge in the treatment of acute myeloid leukemia (AML). Nuclear factor E2-related factor 2 (Nrf2) exerts a vital function in drug resistance of many tumors. Nevertheless, the potential molecular mechanism of Nrf2 regulating the base excision repair pathway that mediates AML chemotherapy resistance remains unclear. Here, in clinical samples, we found that the high expression of Nrf2 and base excision repair pathway gene encoding 8-hydroxyguanine DNA glycosidase (OGG1) was associated with AML disease progression. In vitro, Nrf2 and OGG1 were highly expressed in drug-resistant leukemia cells. Upregulation of Nrf2 in leukemia cells by lentivirus transfection could decrease the sensitivity of leukemia cells to cytarabine, whereas downregulation of Nrf2 in drug-resistant cells could enhance leukemia cell chemosensitivity. Meanwhile, we found that Nrf2 could positively regulate OGG1 expression in leukemia cells. Our chromatin immunoprecipitation assay revealed that Nrf2 could bind to the promoter of OGG1. Furthermore, the use of OGG1 inhibitor TH5487 could partially reverse the inhibitory effect of upregulated Nrf2 on leukemia cell apoptosis. In vivo, downregulation of Nrf2 could increase the sensitivity of leukemia cell to cytarabine and decrease OGG1 expression. Mechanistically, Nrf2-OGG1 axis-mediated AML resistance might be achieved by activating the AKT signaling pathway to regulate downstream apoptotic proteins. Thus, this study reveals a novel mechanism of Nrf2-promoting drug resistance in leukemia, which may provide a potential therapeutic target for the treatment of drug-resistant/refractory leukemia.
化疗耐药是急性髓系白血病 (AML) 治疗中的主要挑战。核因子 E2 相关因子 2 (Nrf2) 在许多肿瘤的耐药性中发挥着重要作用。然而，Nrf2 调节碱基切除修复途径介导 AML 化疗耐药的潜在分子机制尚不清楚。在这里，在临床样本中，我们发现 Nrf2 和编码 8-羟基鸟嘌呤 DNA 糖苷酶 (OGG1) 的碱基切除修复途径基因的高表达与 AML 疾病进展有关。在体外，耐药白血病细胞中 Nrf2 和 OGG1 表达水平较高。通过慢病毒转染上调白血病细胞中的 Nrf2 可降低白血病细胞对阿糖胞苷的敏感性，而下调耐药细胞中的 Nrf2 可增强白血病细胞的化疗敏感性。同时，我们发现 Nrf2 可正向调节白血病细胞中的 OGG1 表达。我们的染色质免疫沉淀实验表明，Nrf2 可与 OGG1 启动子结合。此外，使用 OGG1 抑制剂 TH5487 可部分逆转上调 Nrf2 对白血病细胞凋亡的抑制作用。在体内，下调 Nrf2 可增加白血病细胞对阿糖胞苷的敏感性并降低 OGG1 表达。从机制上讲，Nrf2-OGG1 轴介导的 AML 耐药性可能通过激活 AKT 信号通路来调节下游凋亡蛋白来实现。因此，本研究揭示了 Nrf2 促进白血病耐药的新机制，可为治疗耐药/难治性白血病提供潜在的治疗靶点。
