Down-regulation of P-glycoprotein expression by sustained intracellular acidification in K562/DOX cells
Down-regulation of P-glycoprotein expression by sustained intracellular acidification in K562/DOX cells
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K562/DOX 细胞中持续胞内酸化下调 P-糖蛋白表达
DOI：
10.1016/j.bbrc.2008.10.005
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发表时间：
2008-12-12
影响因子：
3.1
通讯作者：
Wakabayashi, Shigeo
中科院分区：
文献类型：
--
作者：
Lu, Ying;Pang, Tianxiang;Wakabayashi, Shigeo
我们研究了K562/DOX细胞内pH（pH（i））对P-糖蛋白（P-gp）的调节作用。使用选择性Na +/H+交换剂1（NHE1）抑制剂cariporide和"高K +"缓冲液来诱导K562/DOX细胞的持续细胞内酸化，所述K562/DOX细胞表现出比K562细胞更碱性的pHi。酸化导致K562/DOX细胞P-gp活性降低，Rh123蓄积增加，P-gp抑制剂维拉帕米可阻断Rh123蓄积。酸化降低了MDR1 mRNA和P-gp的表达，促进了阿霉素在细胞核内的蓄积和分布。有趣的是，这些过程都是pHi和时间依赖性的。此外，P-gp表达的变化是可逆的pHi恢复。这些结果表明，细胞内持续酸化可通过调控P-gp的表达和活性逆转P-gp介导的肿瘤多药耐药（MDR），且pHi与P-gp在K562/DOX细胞中存在调节联系。(C)2008年爱思唯尔公司All rights reserved.
We have investigated the involvement of intracellular pH (pH(i)) in the regulation of P-glycoprotein (P-gp) in K562/DOX cells. The selective Na+/H+ exchanger1 (NHE1) inhibitor cariporide and the "high K+" buffer were used to induce the sustained intracellular acidification of the K562/DOX cells that exhibited more alkaline pHi than the K562 cells. The acidification resulted in the decreased P-gp activity with increased Rhodamine 123 (Rh123) accumulation in K562/DOX cells, which could be blocked by the P-gp inhibitor verapamil. Moreover, the acidification decreased MDR1 mRNA and P-gp expression, and promoted the accumulation and distribution of doxorubicin into the cell nucleus. Interestingly, these processes were all pHi and time-dependent. Furthermore, the change of the P-gp expression was reversible with the pHi recovery. These data indicate that the tumor multidrug resistance (MDR) mediated by P-gp could be reversed by sustained intracellular acidification through clown-regulating the P-gp expression and activity, and there is a regulative link between the pHi and P-gp in K562/DOX cells. (C) 2008 Elsevier Inc. All rights reserved.