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Nrf2 过表达通过抑制复制因子 C4 增加急性髓系白血病对阿糖胞苷的耐药性。

Nrf2 overexpression increases the resistance of acute myeloid leukemia to cytarabine by inhibiting replication factor C4.

机构信息

College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China.

Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guiyang, Guizhou, China.

出版信息

Cancer Gene Ther. 2022 Nov;29(11):1773-1790. doi: 10.1038/s41417-022-00501-1. Epub 2022 Jul 15.

DOI:10.1038/s41417-022-00501-1
PMID:35840666
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9663296/
Abstract

Drug resistance is a key factor in the treatment failure of acute myeloid leukemia (AML). Nuclear factor E2-related factor 2 (Nrf2) plays a crucial role in tumor chemotherapy resistance. However, the potential mechanism of Nrf2 regulating DNA mismatch repair (MMR) pathway to mediate gene-instability drug resistance in AML is still unclear. Here, it was found that Nrf2 expression was closely related to the disease progression of AML as well as highly expressed in AML patients with poor prognostic gene mutations. Meanwhile, it was also found that the expression of Nrf2 was significantly negatively correlated with DNA MMR gene replication factor C4 (RFC4) in AML. CHIP analysis combined with luciferase reporter gene results further showed that Nrf2 may inhibit the expression of RFC4 by its interaction with the RFC4 promoter. In vitro and vivo experiments showed that the overexpression of Nrf2 decreased the killing effect of chemotherapy drug cytarabine (Ara-C) on leukemia cells and inhibited the expression of RFC4. Mechanistically, The result that Nrf2-RFC4 axis mediated AML genetic instability drug resistance might be received by activating the JNK/NF-κB signaling pathway. Taken together, these findings may provide a new idea for improving AML drug resistance.

摘要

耐药性是急性髓系白血病（AML）治疗失败的关键因素。核因子 E2 相关因子 2（Nrf2）在肿瘤化疗耐药中起着至关重要的作用。然而，Nrf2 调节 DNA 错配修复（MMR）途径以介导 AML 中基因不稳定性耐药的潜在机制尚不清楚。在这里，研究发现 Nrf2 的表达与 AML 的疾病进展密切相关，并且在 AML 患者中表达水平较高，这些患者具有预后不良的基因突变。同时，还发现 Nrf2 的表达与 AML 中 DNA MMR 基因复制因子 C4（RFC4）呈显著负相关。CHIP 分析结合荧光素酶报告基因结果进一步表明，Nrf2 可能通过与 RFC4 启动子相互作用抑制 RFC4 的表达。体外和体内实验表明，Nrf2 的过表达降低了化疗药物阿糖胞苷（Ara-C）对白血病细胞的杀伤作用，并抑制了 RFC4 的表达。在机制上，Nrf2-RFC4 轴通过激活 JNK/NF-κB 信号通路介导 AML 遗传不稳定性耐药。总之，这些发现可能为改善 AML 耐药性提供新的思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/a8266259d0a7/41417_2022_501_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/9dd7bff7a10f/41417_2022_501_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/a8266259d0a7/41417_2022_501_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/708a85062eb2/41417_2022_501_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/35bd6373447f/41417_2022_501_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/36e37aa50696/41417_2022_501_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/e973f8b3dfb8/41417_2022_501_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/50b38d93e77d/41417_2022_501_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/fe61b9b47c66/41417_2022_501_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/9dd7bff7a10f/41417_2022_501_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4229/9663296/a8266259d0a7/41417_2022_501_Fig8_HTML.jpg

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