Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line
Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line
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DOI：
10.1007/s00280-004-0767-4
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发表时间：
2004-06-01
影响因子：
3
通讯作者：
Lung, ML
中科院分区：
文献类型：
--
作者：
Chan, KT;Lung, ML
化疗耐药是肝细胞癌治疗中的主要问题。某些p53突变体可能会增强癌细胞的耐药性。为了确定两种常见的p53突变体R248 Q和R273 C是否会增加肝癌细胞的耐药性，通过用突变型p53表达载体转染p53缺失的Hep 3B细胞，然后用抗癌药物阿霉素和紫杉醇处理它们来建立表达这些特异性p53突变体的稳定细胞系。与仅表达载体的对照细胞相比，表达p53突变体R248 Q但不表达R273 C的细胞显示出对两种药物的交叉耐药性。此外，在p53突变体R248 Q表达细胞中，多药耐药基因产物P-糖蛋白的表达和活性均升高。在R248 Q表达细胞中也观察到多柔比星摄取减少。这些结果表明，在肝癌细胞中表达的p53突变体，R248 Q，可能会提高他们的耐药性和P-糖蛋白活性的上调可能有助于这种保护作用。
Chemoresistance is a major problem in the treatment of hepatocellular carcinoma. Certain p53 mutants may enhance drug resistance in cancer cells. To determine whether two frequently occurring p53 mutants, R248Q and R273C, would increase the drug resistance of liver cancer cells, stable cell lines expressing these specific p53 mutants were established by transfecting the p53-null Hep3B cells with mutant p53 expression vectors, and then treating them with the anticancer drugs doxorubicin and paclitaxel. The cells expressing the p53 mutant, R248Q, but not R273C, displayed cross-resistance to both drugs, in contrast to the control cells expressing the vector alone. Moreover, both the expression and the activity of the multiple drug resistance gene product, P-glycoprotein, were elevated in p53 mutant R248Q-expressing cells. Reduced uptake of doxorubicin was also observed in the R248Q-expressing cells. These results suggest that expression of the p53 mutant, R248Q, in liver cancer cells may enhance their drug resistance and that upregulation of P-glycoprotein activity may contribute to this protective effect.