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Inhibition of the Nrf2-TrxR Axis Sensitizes the Drug-Resistant Chronic Myelogenous Leukemia Cell Line K562/G01 to Imatinib Treatments
preprintsubmitted on 31.08.2019, 04:40 and posted on 03.09.2019, 14:28 by Lianrong Xu, Yan Zhao, Fei Pan, Mengxia Zhu, Liqin Yao, Yan Liu, Jiangfang Feng, Jie Xiong, Xiuhua Chen, Fanggang Ren, Yanhong Tan, Hongwei Wang
Nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in tumor drug resistance, but its role in imatinib-resistance of chronic myeloid leukemia (CML) remains elusive. We aimed to investigate the effects of Nrf2 on drug sensitivity, thioredoxin reductase (TrxR) expression, reactive oxygen species (ROS) production, apoptosis induction in imatinib-resistant CML K562/G01 cells and explored their potential mechanisms. Stable K562/G01 cells with knockdown of Nrf2 were established by infection of siRNA-expressing lentivirus. The mRNA and protein expression levels of Nrf2 and TrxR were determined by real-time quantitative polymerase chain reaction and western blot, respectively. ROS generation and apoptosis were assayed by flow cytometry, while drug sensitivity was measured by Cell Counting Kit-8 assay. Imatinib-resistant K562/G01 cells had higher levels of Nrf2 expression than the parental K562 cells at both mRNA and protein levels. Expression levels of Nrf2 and TrxR were positively correlated in K562/G01 cells. Knockdown of Nrf2 in K562/G01 cells enhanced the intracellular ROS level, suppressed cell proliferation and increased apoptosis in response to imatinib treatments. Nrf2 expression contributes to the imatinib-resistance of K562/G01 cells, and is positively correlated with TrxR expression. Targeted inhibition of the Nrf2-TrxR axis represents a potential therapeutic approach for imatinib-resistant CML.
the Natural Science Foundation of Shanxi [grant numbers 2012011038-5]
Shanxi Medical and Health Science and Technology Plan Project [grant numbers 20100202]