Nrf-2/Gst-alpha mediated imatinib resistance through rapid 4-HNE clearance
Nrf-2/Gst-alpha mediated imatinib resistance through rapid 4-HNE clearance
复制标题
Nrf-2/Gst-alpha 通过快速 4-HNE 清除介导伊马替尼耐药
DOI：
10.1016/j.yexcr.2017.03.004
复制
发表时间：
2017
影响因子：
3.7
通讯作者：
Wang Fang
中科院分区：
文献类型：
--
作者：
Wang Xin;Li Yanqing;Chen Wei;Wang Yawen;Hui Lingyun;Liu Juan;Li Na;Zhang Lin;Zou Yuanwu;Wang Fang
甲酸伊马替尼（imatinib mesylate， IM）的出现极大地改善了慢性髓系白血病患者的预后，但耐药，特别是在疾病晚期，预示着最终的复发和进展。为了确定在IM处理过程中产生耐药的候选分子，通过逐渐增加IM剂量培养产生了耐药的K562细胞系。Nrf-2及其下游靶点Gst-α的表达在这些细胞中被显著诱导。反过来，GST-α通过维持细胞内低水平的4-HNE介导细胞存活。抑制Nrf-2可有效降低Gst-α的表达，导致4-HNE的积累和对IM的敏感性升高。此外，在IM敏感的K562细胞中，强化的Gst-α表达显著地保护细胞免受IM的损伤。最后，我们还检测了临床骨样品中Nrf-2的水平。CML患者骨组织中Nrf-2和Gst-α含量高于健康供者。此外，在IM反应较弱的患者样本中，Nrf-2和Gst-α进一步上调。总之，我们的研究表明，Nrf-2/GST对4-HNE的快速清除可能代表了CML中IM耐药的新分子基础。
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.