Overexpression of Nrf2 Promotes OGG1 Expression By Activating AKT Signaling Pathway to Mediate Cytarabine Resistance in Acute Myeloid Leukemia Cells

Background：Nuclear factor E2 related factor 2 (Nrf2) exerts a vital function in drug resistance of many tumors. Base excision repair (BER) pathway gene 8-hydroxyguanine DNA glycosidase (OGG1) is a key component of tumor drug resistance. Nevertheless, the potential molecular mechanism of its mediating drug resistance in acute myeloid leukemia (AML) remains unclear.

Methods: Firstly, isolation of mononuclear cells from normal healthy donors and AML patients. Drug-resistant AML cell lines were cultured by increasing drug concentration, and AML cell lines with up-regulation and down-regulation of Nrf2 were constructed by lentivirus transfection. The possible mechanism of drug resistance of leukemic cells mediated by overexpression of Nrf2 was investigated by CCK-8 method, immunofluorescence, immunocytochemistry, immunohistochemistry, flow cytometry, Chromatin immunoprecipitation, Western blot, xenograft mouse model and so on.

Results: In clinical samples, we found that the expression of Nrf2 and OGG1 were higher in patients with relapse AML. At the cellular level, we confirmed that up-regulation of Nrf2 increased the expression of OGG1, decreased the sensitivity of leukemic cells to cytarabine, and activated the AKT signaling pathway. However, after down-regulation of Nrf2, the expression of OGG1 decreased, the sensitivity of leukemic cells to cytarabine increased and the expression of phosphorylated AKT decreased. MK-2206, an inhibitor of AKT pathway, can inhibit the activation of AKT signaling pathway, decrease the expression of OGG1 and increase the expression of apoptotic protein. In the case of overexpression of Nrf2, the use of OGG1 inhibitors can increase the sensitivity of AML cells to cytarabine. In vivo, we found that the expression of OGG1 decreased after down-regulation of Nrf2, which had a certain protective effect on xenografted tumor mice.

Conclusion: overexpression of Nrf2 may promote the expression of OGG1 and mediate drug resistance in AML cells by activating AKT signal pathway. In order to prevent the progression of AML cells, blocking AKT signal pathway with MK-2206 or targeting OGG1 inhibitors may be a potential therapeutic strategy for AML resistance.

No relevant conflicts of interest to declare.