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

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...

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Published in:	The Journal of biological chemistry 2023-01, Vol.299 (1), p.102798-102798, Article 102798
Main Authors:	Shang, Qin, Pan, Chengyun, Zhang, Xi, Yang, Tonghua, Hu, Tianzhen, Zheng, Lin, Cao, Shuyun, Feng, Cheng, Hu, Xiuying, Chai, Xiao, Wang, Jishi, Fang, Qin
Format:	Article
Language:	eng
Subjects:	8-hydroxyguanine DNA glycosidase acute myeloid leukemia Apoptosis Cell Nucleus - metabolism cytarabine Cytarabine - therapeutic use DNA Glycosylases - metabolism Drug Resistance, Neoplasm Humans Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism nuclear factor E2–related factor 2 Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism resistance
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Summary:	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.
ISSN:	0021-9258 1083-351X