Visfatin mediates doxorubicin resistance in human non-small-cell lung cancer via Akt-mediated up-regulation of ABCC1
Visfatin mediates doxorubicin resistance in human non-small-cell lung cancer via Akt-mediated up-regulation of ABCC1
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DOI：
10.1111/cpr.12366
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发表时间：
2017-10-01
影响因子：
8.5
通讯作者：
Li, Shanqing
中科院分区：
文献类型：
--
作者：
Cao, Zhili;Liang, Naixin;Li, Shanqing
目的非小细胞肺癌（NSCLC）是世界范围内癌症死亡的主要原因之一。内脂素水平升高与NSCLC临床预后不良相关。材料与方法采用CCK-8试剂盒检测内脂素对耐药细胞的作用。基因和蛋白质的变化分别通过实时PCR和Western blot analysis.ResultsOur目前的数据证实，内脂素的表达显着增加，在NSCLC细胞和组织。此外，与相应的敏感性亲代细胞相比，多柔比星（Dox）耐药的非小细胞肺癌细胞中内脂素的蛋白质和mRNA表达显着升高。内脂素过表达可下调NSCLC细胞对阿霉素的敏感性，上调ABCC 1的mRNA和蛋白表达，而对ABCB 1无影响。内脂素的敲低可下调阿霉素耐药NSCLC细胞中ABCC 1的表达。内脂素可增加Akt在NSCLC细胞中的磷酸化和核定位。LY 294002可降低NSCLC Dox耐药细胞多药耐药蛋白1（MRP 1）的表达。染色质免疫沉淀实验表明，内脂素过表达可显著增加A549和H1793细胞中Akt与ABCC 1启动子的结合，提示内脂素可通过激活Akt/MRP 1降低NSCLC细胞对阿霉素的敏感性。这表明抑制内脂素信号可能是一种有希望的治疗策略，用于管理NSCLC患者的化疗耐药性。
ObjectivesNon-small-cell lung cancer (NSCLC) is one of the leading causes of cancer deaths worldwide. Increasing levels of visfatin are correlated with worse clinical prognosis of NSCLC. However, the effects of visfatin on drug resistant are still not well illustrated.Materials and methodsEffects of visfatin on drug resistant cells were checked by CCK-8 kit. Gene and protein variations were measured by real-time PCR and western blot analysis, respectively.ResultsOur present data confirmed that expression of visfatin was significantly increased in NSCLC cells and tissues. In addition, protein and mRNA expression of visfatin were significantly elevated in doxorubicin (Dox) resistance of NSCLC cells when compared with their corresponding sensitivity parental cells. Overexpression of visfatin can down-regulate the Dox sensitivity of NSCLC cells and up-regulate the mRNA and protein expression of ABCC1, while has no effect on ABCB1. Knockdown of visfatin can down-regulate the expression of ABCC1 in Dox-resistant NSCLC cells. Visfatin can increase the phosphorylation and nuclear localization of Akt in NSCLC cells. LY294002 can decrease the expression of multidrug resistance protein-1 (MRP1) in NSCLC Dox-resistant cells. Chromatin immunoprecipitation assays showed that overexpression of visfatin can significantly increase the binding of Akt with the promoter of ABCC1 in both A549 and H1793 cells.ConclusionsThese data showed that visfatin can decrease Dox sensitivity of NSCLC cells via activation of Akt/MRP1. It indicated that inhibition of visfatin signals might be a promising therapeutic strategy for the management of chemoresistance of NSCLC patients.