title: Nrf-2/Gst-α mediated imatinib resistance through rapid 4-HNE clearance.
abstract: The advent of imatinib mesylate (IM) has dramatically improved the outcome of patients with chronic myeloid leukemia, but drug resistance, particularly in advanced stage of disease, portents eventual relapse and progression. To identify the candidate molecule responsible for resistance during IM treatment, an IM-resistant K562 cell line was generated by culturing in gradually increasing dose of IM. The expression of Nrf-2 and its downstream target, Gst-α, were significantly induced in these cells. GST-α, in turn, mediated cell survival by maintaining intracellular low level of 4-HNE. Inhibition of Nrf-2 effectively reduced the expression of Gst-α, resulting in accumulation of 4-HNE and elevated sensitiveness to IM. Moreover, in IM-sensitive K562 cells enforced Gst-α expression strikingly protected cells from the insult of IM. Finally, we also examined the levels of Nrf-2 in clinical bone morrow samples. Nrf-2 and Gst-α were more abundant in bone morrow of CML patients compared with that of healthy donors. In addition, Nrf-2 and Gst-α were further up-regulated in samples of patients with weak response to IM. In conclusion, our study shows that rapid clearance of 4-HNE by Nrf-2/GST may represents a novel molecular basis of IM resistance in CML.
authors.affiliation: Department of Pharmacy, The Second Affiliated Hospital of Xi'an Medical College, Xi'an 710038, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
authors.forename: Yawen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Hui
authors.affiliation: Department of Hematology，The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, The Tuberculosis Prevention and Care Hospital of Shannxi, Xi'an 710100, People's Republic of China.
authors.forename: Yuanwu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China. Electronic address: wfang1823@xjtu.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
mesh_terms: D000328:Adult; D000447:Aldehydes / Q000008:administration & dosage; D001854:Bone Marrow Cells; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000447:Aldehydes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000068877:Imatinib Mesylate; C484555:GSTA1 protein, human; D005982:Glutathione Transferase; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxynonenal (4-HNE); Chronic myeloid leukemia (CML); Glutathione S-transferase (GST); Nuclear factor erythroid-2 related factor 2 (Nrf-2); TKI resistance