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

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          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.

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          Acute Myeloid Leukemia.

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            Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.

            Ferroptosis is a recently recognized form of regulated cell death caused by an iron-dependent accumulation of lipid reactive oxygen species. However, the molecular mechanisms regulating ferroptosis remain obscure. Here, we report that nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. Additionally, nuclear NRF2 interacted with transcriptional coactivator small v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog proteins such as MafG and then activated transcription of quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1. Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib. Furthermore, genetic or pharmacologic inhibition of NRF2 expression/activity in HCC cells increased the anticancer activity of erastin and sorafenib in vitro and in tumor xenograft models.
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              NRF2 and the Hallmarks of Cancer

              The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor. In this review, we explore the roles of NRF2 in the hallmarks of cancer, indicating both tumor suppressive and tumor-promoting effects.
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                Author and article information

                Contributors
                wangjishi9646@163.com
                fangqin@gmc.edu.cn
                Journal
                Cancer Gene Ther
                Cancer Gene Ther
                Cancer Gene Therapy
                Nature Publishing Group US (New York )
                0929-1903
                1476-5500
                15 July 2022
                15 July 2022
                2022
                : 29
                : 11
                : 1773-1790
                Affiliations
                [1 ]GRID grid.413458.f, ISNI 0000 0000 9330 9891, College of Pharmacy, Guizhou Medical University, ; Guiyang, Guizhou China
                [2 ]GRID grid.452244.1, Department of Haematology, , Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, ; Guiyang, Guizhou China
                [3 ]GRID grid.413458.f, ISNI 0000 0000 9330 9891, School of Basic Medical Sciences, , Guizhou Medical University, ; Guiyang, Guizhou China
                [4 ]GRID grid.452244.1, pharmacy department, , Affiliated Hospital of Guizhou Medical University, ; Guiyang, Guizhou China
                Author information
                http://orcid.org/0000-0002-8642-3447
                http://orcid.org/0000-0001-5118-6990
                http://orcid.org/0000-0001-9492-5204
                Article
                501
                10.1038/s41417-022-00501-1
                9663296
                35840666
                2d736298-5859-4aeb-95f4-b0d14f6e7881
                © The Author(s) 2022, corrected publication 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 February 2022
                : 11 June 2022
                : 23 June 2022
                Funding
                Funded by: Cultivation project of National Natural Science Foundation of Guizhou Medical University (20NSP027)
                Funded by: National Natural Science Foundation of China(82060026)
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 82170168
                Award Recipient :
                Funded by: Translational Research Grant of National Clinical Research Center for Hematologic Diseases (2021WWB01). National Natural Science Foundation of China(81960032)
                Categories
                Article
                Custom metadata
                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2022

                Oncology & Radiotherapy
                leukaemia,gene expression
                Oncology & Radiotherapy
                leukaemia, gene expression

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