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CK2抑制剂CX4945对肺癌A549/DDP细胞顺铂耐药性的逆转作用

CK2 inhibitor CX4945 reverses cisplatin-resistance of lung cancer A549/DDP cells
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摘要 目的 :探讨蛋白激酶CK2(casein kinase 2,曾称酪蛋白激酶Ⅱ)抑制剂CX4945对顺铂(cisplatin,DDP)耐药性肺癌A549/DDP细胞生长活性的影响及其可能的作用机制。方法 :CCK-8法检测肺癌A549细胞及其耐药性A549/DDP细胞的DDP半数抑制浓度(half maximal inhibitory concentration,IC50),以及抑制剂CX4945对A549/DDP细胞耐药性的影响。蛋白质印迹法检测A549及A549/DDP细胞在DDP干预前后Wnt信号通路相关蛋白(CK2α、β-catenin和cyclin D1)、耐药相关蛋白[多药耐药相关蛋白1(multidrug resistance-associated protein 1,MRP1)和肺耐药相关蛋白(lung resistance-related protein,LRP)]和凋亡相关蛋白[剪切型半胱天冬酶-3(cleaved caspase-3,c-caspase-3)]的表达变化。将A549/DDP细胞分为未处理对照组、CX4945组、DDP组及CX4945+DDP组,各组药物处理后,采用蛋白质印迹法和FCM法分别检测Wnt信号通路、耐药及凋亡相关蛋白的表达以及细胞凋亡情况。结果:DDP对A549/DDP细胞的IC50值是A549细胞的4.59倍,并在CX4945预处理后A549/DDP细胞耐药性明显降低(P <0.001)。与A549细胞相比,A549/DDP细胞中CK2α、β-catenin、cyclin D1、MRP1和LRP蛋白的表达水平明显较高,并在DDP处理后进一步升高(P值均<0.001);然而A549细胞中,DDP处理后CK2α、β-catenin和cyclin D1蛋白表达水平明显降低(P值均<0.01),而MRP1和LRP蛋白表达则无明显变化(P值均>0.05)。与未处理对照组和DDP组相比,CX4945组和CX4945+DDP组的A549/DDP细胞中β-catenin、cyclin D1、MRP1和LRP蛋白表达水平均明显降低(P值均<0.01)。此外,CX4945+DDP组的A549/DDP细胞凋亡率和c-caspase-3表达水平均较未处理对照组和DDP组明显升高(P值均<0.001)。结论 :CK2抑制剂CX4945可通过抑制Wnt通路,降低耐药相关蛋白的表达,从而逆转肺癌A549/DDP细胞的顺铂耐药性。 Objective:To investigate the effect of CK2(casein kinase 2)inhibitor CX4945 on the cisplatin(DDP)-resistance of lung cancer A549/DDP cells and the underlying molecular mechanism.Methods:The CCK-8 assay was used to detect the half maximal inhibitory concentration(IC50)of DDP in lung cancer A549 and A549/DDP cells,and to compare the DDP-resistance of two cell lines.The effect of CX4945 on DDP-resistance of A549/DDP cells was tested by CCK-8 method.Western blotting was used to detect the expressions of Wnt signaling pathway-related proteins(CK2α,β-catenin and cyclin D1),drug resistance-related proteins[multidrug resistance-associated protein 1(MRP1)and lung resistance-related protein(LRP)]and apoptosis-related protein[cleaved caspase-3(c-caspase-3)]in A549 and A549/DDP cells treated with DDP or not.The A549/DDP cells were treated with no drug(as the control group),CX4945,DDP and their combination(as CX4945+DDP group),then the expressions of Wnt signaling pathway-,drug resistance-and apoptosis-related proteins were detected by Western blotting,and the apoptosis of A549/DDP cells was detected by FCM method.Results:The IC50 value of DDP in A549/DDP cells was 4.59 times higher than that in A549 cells,and the DDP-resistance of A549/DDP cells was decreased by CX4945 pretreatment(P<0.001).The expression levels of CK2α,β-catenin,cyclin D1,MRP1 and LRP proteins were significantly increased in A549/DDP cells as compared with A549 cells(all P<0.001),and the levels of these proteins in A549/DDP cells were further increased after DDP treatment(all P<0.001).In A549 cells after treatment with DDP,the expression levels of CK2α,β-catenin and cyclin D1 proteins were reduced(all P<0.01),but the levels of MRP1 and LRP proteins were not significantly changed(both P>0.05).Compared with the control group and DDP group,the expression levels ofβ-catenin,cyclin D1,MRP1 and LRP proteins in A549/DDP cells of CX4945 group and CX4945+DDP group were significantly declined(all P<0.01).In addition,the apoptosis rate of A549/DDP cells and the
作者 金承基 宋萍 郑金旭 孙金玲 徐莉莉 JIN Chengji;SONG Ping;ZHENG Jinxu;SUN Jinling;XU Lili(Department of Respiratory Medicine,Affiliated Hospital of Jiangsu University,Zhenjiang 212001,Jiangsu Province,China)
出处 《肿瘤》 CAS CSCD 北大核心 2019年第1期10-18,40共10页 Tumor
基金 江苏大学附属医院科技项目(编号:jdfyRc2015013) 镇江市社会发展科技支撑计划项目(编号:SH2013033).
关键词 非小细胞肺 抗药性 肿瘤 WNT信号通路 顺铂 酪蛋白激酶Ⅱ CX4945 Carcinoma,non-small cell lung Drug resistance,neoplasm Wnt signaling pathway Cisplatin Casein kinase 2 CX4945
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