2. Academic Validation
  3. Nuclear factor Nrf2 promotes glycosidase OGG1 expression by activating the AKT pathway to enhance leukemia cell resistance to cytarabine

Nuclear factor Nrf2 promotes glycosidase OGG1 expression by activating the AKT pathway to enhance leukemia cell resistance to cytarabine

  • J Biol Chem. 2022 Dec 14;102798. doi: 10.1016/j.jbc.2022.102798.
Qin Shang 1,  Chengyun Pan 2,  Xi Zhang 3,  Tonghua Yang 4,  Tianzhen Hu 5,  Lin Zheng 6,  Shuyun Cao 2,  Cheng Feng 6,  Xiuying Hu 2,  Xiao Chai 2,  Jishi Wang 7,  Qin Fang 8
Affiliations

Affiliations

  • 1 College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China; Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China.
  • 2 Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China.
  • 3 Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China.
  • 4 Yunnan Blood Disease Clinical Medical Center, Yunnan Blood Disease Hospital, National Key Clinical Specialty of Hematology, Department of Hematology, The First People's Hospital of Yunnan Province, Kunming, China.
  • 5 College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China.
  • 6 Department of Clinical Medical School, Guizhou Medical University, Guiyang, Guizhou, China.
  • 7 Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China; Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China; National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: wangjishi9646@163.com.
  • 8 College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China; Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China. Electronic address: fangqin@gmc.edu.cn.
PMID: 36528059 DOI: 10.1016/j.jbc.2022.102798
Abstract

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 (BER) pathway that mediates AML chemotherapy resistance remains unclear. Here, in clinical samples, we found that the high expression of Nrf2 and BER 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 cell. Up-regulation of Nrf2 in leukemia cell by lentivirus transfection could decrease the sensitivity of leukemia cell to cytarabine, while down-regulation of Nrf2 in drug-resistant cells could enhance leukemia cell chemosensitivity. Meanwhile, we found that Nrf2 could positively regulate OGG1 expression in leukemia cell. Our ChIP 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 up-regulated Nrf2 on leukemia cell Apoptosis. In vivo, down-regulation 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.

Keywords

8-hydroxyguanine DNA glycosidase; acute myeloid leukemia; cytarabine; nuclear factor E2 related factor 2; resistance.

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