SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell
SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell
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SET介导的NDRG1抑制参与人肺癌细胞上皮间质转化表型的获得和顺铂耐药
DOI：
10.1016/j.cellsig.2014.08.010
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发表时间：
2014-12-01
影响因子：
4.8
通讯作者：
He, Zhimin
中科院分区：
文献类型：
--
作者：
Liu, Hao;Gu, Yixue;He, Zhimin
对治疗的耐药性的发展仍然是肺癌管理中的一个严重的临床问题。经历上皮-间充质转化（EMT）的癌细胞已被证明在对化疗的抗性中起作用。在这里，我们利用蛋白质组学为基础的方法，并确定了一个显着下调的转移抑制NDRG 1耐药肺癌细胞。我们发现DNRG 1的下调构成了获得EMT表型的机制，并赋予肺癌细胞对顺铂的耐药性增加。我们还鉴定了一个信号级联，即SET-竖条PP 2A-竖条c-myc-竖条NDRG 1，其中SET的上调对于NDRG 1的抑制至关重要。我们还发现，通过FTY 720阻断SET（或PP 2A的再活化）可逆转EMT，恢复药物敏感性，并抑制肺肿瘤异种移植物的侵袭性和生长。总之，我们的研究结果表明SET介导的NDRG 1调节与EMT表型和耐药性的获得之间存在功能联系，并提供了证据表明，SET驱动的EMT的阻断可以克服耐药性并抑制肿瘤进展。(C)2014爱思唯尔公司All rights reserved.
Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. Cancer cells undergoing epithelial-to-mesenchymal transition (EMT) have been shown to play roles in resistance to chemotherapy. Here, we utilized a proteomics-based method and identified a significant downregulation of the metastasis suppressor NDRG1 in drug resistant lung cancer cells. We showed that downregulation of DNRG1 constitutes a mechanism for acquisition of EMT phenotype and endows lung cancer cells with an increased resistance to cisplatin. We also identified a signal cascade, namely, SET--vertical bar PP2A-vertical bar c-myc--vertical bar NDRG1, in which upregulation of SET is critical for inhibition of NDRG1. We also found that blockade of SET (or reactivation of PP2A) by FTY720 reverted EMT, restored drug sensitivity, and inhibited invasiveness and growth of lung tumor xenografts. Together, our results indicated a functional link between SET-mediated NDRG1 regulation and acquisition of EMT phenotype and drug resistance, and provided an evidence that blockade of SET-driven EMT can overcome drug resistance and inhibit tumor progression. (C) 2014 Elsevier Inc. All rights reserved.