Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells
Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells
复制标题
p38-MAPK 增加导致人胃癌细胞对化疗产生耐药性
DOI：
10.1186/1471-2407-8-375
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发表时间：
2008-12-18
期刊：
影响因子：
3.8
通讯作者：
Wei, Lixin
中科院分区：
文献类型：
--
作者：
Guo, Xianling;Ma, Nannan;Wei, Lixin
化疗耐药是癌症成功治疗的主要障碍之一，通常与多药耐药（MDR）有关。已经提出了许多不同的机制来解释癌细胞中耐多药表型的发展。目前研究最多的机制之一是p -糖蛋白（P-gp）的过表达，p -糖蛋白是themdr1基因的产物。肿瘤细胞通常由于themdr1基因的上调而获得耐药表型。mdr1基因过表达常见于原发性胃腺癌。方法研究p38-MAPK信号通路在长春新碱耐药SGC7901/VCR细胞中的作用。Western blot和RT-PCR检测P-gp和MDR1 RNA。Western blot和流式细胞仪检测P-gp活化蛋白激酶和功能。双荧光素酶报告基因法和膜联蛋白V-PI双染色检测Ap-1活性和细胞凋亡。结果耐长春新碱的SGC7901/VCR细胞对p- gp相关药物和p- gp无关药物均有耐药，MDR1基因表达增加。在耐药细胞中也发现磷酸化p38-MAPK和AP-1活性的组成性增加。SB202190抑制p38-MAPK可降低活化蛋白-1 （AP-1）活性和mdr1表达水平，增加SGC7901/VCR细胞对化疗的敏感性。结论p38-MAPK通路的激活可能参与了SGC7901/VCR细胞株p -糖蛋白介导和p -糖蛋白非介导多药耐药的调控。
BackgroundChemoresistance is one of the main obstacles to successful cancer therapy and is frequently associated with Multidrug resistance (MDR). Many different mechanisms have been suggested to explain the development of an MDR phenotype in cancer cells. One of the most studied mechanisms is the overexpression of P-glycoprotein (P-gp), which is a product of theMDR1gene. Tumor cells often acquire the drug-resistance phenotype due to upregulation of theMDR1gene. Overexpression ofMDR1gene has often been reported in primary gastric adenocarcinoma.MethodsThis study investigated the role of p38-MAPK signal pathway in vincristine-resistant SGC7901/VCR cells. P-gp and MDR1 RNA were detected by Western blot analysis and RT-PCR amplification. Mitgen-activated protein kinases and function of P-gp were demonstrated by Western blot and FACS Aria cytometer analysis. Ap-1 activity and cell apoptosis were detected by Dual-Luciferase Reporter Assay and annexin V-PI dual staining.ResultsThe vincristine-resistant SGC7901/VCR cells with increased expression of the multidrug-resistance 1 (MDR1) gene were resistant to P-gp-related drug and P-gp-unrelated drugs. Constitutive increases of phosphorylated p38-MAPK and AP-1 activities were also found in the drug-resistant cells. Inhibition of p38-MAPK by SB202190 reduced activator protein-1 (AP-1) activity andMDR1expression levels and increased the sensitivity of SGC7901/VCR cells to chemotherapy.ConclusionActivation of the p38-MAPK pathway might be responsible for the modulation of P-glycoprotein-mediated and P-glycoprotein-unmediated multidrug resistance in the SGC7901/VCR cell line.