细胞内酸化对白血病耐药细胞P-糖蛋白的影响
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摘要
背景:由P-糖蛋白(P-gp)介导的肿瘤多药耐药(MDR)是影响肿瘤化疗效果的重要原因。临床上白血病初次化疗一般可取得较好的结果,但复发后产生耐药性的肿瘤细胞则疗效较差。肿瘤细胞的MDR是由一种药物诱发,引起对其它多种不同结构的药物同时产生交叉耐药,导致一些联合化疗方案的失败。多药耐药产生的机制比较复杂,其中P-gp的过度表达是最重要的原因。由MDR1基因编码的P-gp具有复杂的膜转运功能,可以利用ATP水解释放的能量主动地将疏水亲脂性药物转运到细胞外,导致细胞内药物浓度低于杀伤浓度;还可以使药物再分布到非靶细胞器从而导致耐药。多年来,对于逆转MDR的研究大多局限于如何抑制或拮抗耐药基因表达及耐药相关蛋白功能方面,目前已有的钙通道阻断剂、钙调蛋白抑制剂、类固醇激素、环孢霉素等药物往往都由于高毒性或特异性差等原因难于应用到临床。近期有很多研究证实,细胞内pH值增高是很多耐药肿瘤细胞所具有的共同改变,这一特点为肿瘤MDR研究提供了一个新的方向。但耐药肿瘤细胞内pH值与P-gp的关系仍不明确,这方面需要深入探讨。
目的:本研究通过降低K562/A02耐药细胞内pH,观察细胞酸化对P-gp的影响,探讨耐药肿瘤细胞内pH值与P-gp的关系,为明确二者关系提供实验依据,并且为逆转肿瘤多药耐药提供新的方法。
方法:应用高钾缓冲溶液和钠氢交换蛋白1(NHE1)的特异性抑制剂酸化细胞,降低细胞内pH值。采用MTT法观察高钾缓冲溶液和NHE1的特异性抑制剂诱导的细胞内酸化对细胞活力的影响。应用激光共聚焦显微镜测定K562及K562/A02细胞内pH值。分别采用实时定量RT-PCR技术及Westem blot检测细胞酸化对P-gp的mRNA表达水平和蛋白表达水平的影响。应用流式细胞仪检测细胞酸化对K562/A02细胞P-gp功能的影响。应用激光共聚焦显微镜观察细胞酸化对阿霉素在K562及K562/A02细胞内累积和分布的影响,采用Western blot方法检测酸化过程对p38,ERK,JNK蛋白激酶的影响。
结果:细胞酸化3小时对K562及K562/A02细胞的活力影响较小。P-gp阴性的K562细胞的胞内pH值显著低于P-gp阳性的K562/A02细胞。细胞酸化还分别在蛋白水平和mRNA水平抑制了K562/A02细胞中P-gp的表达,并且这种抑制具有细胞内pH及酸化时间的依赖性。在K562/A02细胞中,P-gp的功能随细胞内pH的降低而减弱,细胞酸化明显增加了K562/A02细胞内罗丹明123(Rh123)的累积,并抑制了P-gp介导的Rh123外排。细胞酸化增加了K562/A02细胞内阿霉素的累积,并且这种增加具有pH值依赖性,随着酸化程度的加深细胞内阿霉素的累积也逐渐增加,阿霉素在细胞核内的分布也明显增多。随着细胞内pH的降低,K562/A02细胞中p38蛋白激酶磷酸化水平呈下降趋势,ERK蛋白激酶磷酸化水平呈上升趋势,JNK蛋白激酶磷酸化水平呈上升趋势。当应用ERK蛋白激酶抑制剂时,细胞酸化可诱导1938蛋白激酶磷酸化水平上升,对JNK蛋白激酶磷酸化水平未见影响。
结论:细胞酸化能够抑制K562/A02耐药细胞株的MDR1 mRNA转录,同时能够抑制P-gp的蛋白表达和功能,并能够增加阿霉素在耐药细胞中的累积及向细胞核内的分布。其信号转导机制可能是通过增强耐药细胞内ERK蛋白激酶磷酸化水平,间接抑制p38蛋白激酶的磷酸化水平,同时增强JNK蛋白激酶的磷酸化水平,最终下调P-gp的表达与功能。
Background:As the major obstacle of chemotherapy,multidrug resistance(MDR) leads to the chemoresistance and the decreased survival in leukemias.The tumor MDR is induced by one drug and results in the tumor resistance to other drugs and the failure of chemical therapy.The mechanism of MDR is complicate,and one of the most important reasons is the expression of P-gp.The P-gp is encoded by the MDR1 gene,and could transport the lipophilia drugs out of the tumor cells,which results in the decreased therapeutic effect and the redistribution of the anticancer drugs.With the development of P-gp modulators to the third generation,the regulation of pogp is still unsatisfactory.In recent years,it has been reported that cancer cells show a strong tendency towards an alkaline deviation of the entire homeostasis when they are resistant to therapeutic intervention.In order to clarify the internal correlation between pH_i and P-gp in MDR leukemia cells,we tested a potential role for intracellular acidification in reversing of MDR through P-gp regulation.
Objective:The aim of the study was to investigate the effect of intracellular acidification on the P-gp in K562/A02 cells,clarify the relation between intracellular acidification and the P-gp,and provide new strategy to reverse the MDR.
Method:Confocal laser microscope was used to determine the pH_i of the cells,and MTT assay was for determining the cytotoxicity of intracellular acidification on K562 and K562/A02 cells.By using real-time RT-PCR and western blot,the influences of intracellular acidification on P-gp expression at mRNA and protein levels were determined.Flow cytometry was applied to detect the influence of intracellular acidification on the activity of P-gp.Confocal laser microscope was also used to determine the accumulation and distribution of doxorubicin in K562 and K562/A02 cells. Western blot assay was used to detect the effect of intracellular acidification on the expression of P-gp,the phosphorylation level of p38 mitogen-activated protein kinase (MAPK),the extracellular signal regulated kinase(ERK) and the c-Jun amino-terminal kinase(JNK).
Results:The results indicated that intracellular acidification had no obvious cytotoxicity on K562 and K562/A02 cells,and it reduced the level of P-gp in a pH_i and time-dependent manner in K562/A02 cells.This occurred primarily at the mRNA level, which was revealed by real-time RT-PCR analysis.The P-gp expression was also down-regulated by intracellular acidification that revealed by western blot assay.The decrease of P-gp level was associated with a significant increased accumulation, decreased efflux of Rh123 and the increased accumulation of doxorubicin in the K562/A02 cells induced by the intracellular acidification.The phosphorylation level of p38 MAPK was decreased and the phosphorylation level of ERK and JNK was increased by the intracellular acidification.When the inhibitor of ERK was used,the phosphorylation level of p38 MAPK was increased significantly,and the JNK was not affected by the inhibitor.
Conclusions:The data indicated that the intracellular acidification could reverse the MDR of K562/A02 cells through down-regulation of P-gp activity and expression.The intracellular acidification might down-regulated the P-gp expression through MAPK signal transportation pathway.
目的:本研究通过降低K562/A02耐药细胞内pH,观察细胞酸化对P-gp的影响,探讨耐药肿瘤细胞内pH值与P-gp的关系,为明确二者关系提供实验依据,并且为逆转肿瘤多药耐药提供新的方法。
方法:应用高钾缓冲溶液和钠氢交换蛋白1(NHE1)的特异性抑制剂酸化细胞,降低细胞内pH值。采用MTT法观察高钾缓冲溶液和NHE1的特异性抑制剂诱导的细胞内酸化对细胞活力的影响。应用激光共聚焦显微镜测定K562及K562/A02细胞内pH值。分别采用实时定量RT-PCR技术及Westem blot检测细胞酸化对P-gp的mRNA表达水平和蛋白表达水平的影响。应用流式细胞仪检测细胞酸化对K562/A02细胞P-gp功能的影响。应用激光共聚焦显微镜观察细胞酸化对阿霉素在K562及K562/A02细胞内累积和分布的影响,采用Western blot方法检测酸化过程对p38,ERK,JNK蛋白激酶的影响。
结果:细胞酸化3小时对K562及K562/A02细胞的活力影响较小。P-gp阴性的K562细胞的胞内pH值显著低于P-gp阳性的K562/A02细胞。细胞酸化还分别在蛋白水平和mRNA水平抑制了K562/A02细胞中P-gp的表达,并且这种抑制具有细胞内pH及酸化时间的依赖性。在K562/A02细胞中,P-gp的功能随细胞内pH的降低而减弱,细胞酸化明显增加了K562/A02细胞内罗丹明123(Rh123)的累积,并抑制了P-gp介导的Rh123外排。细胞酸化增加了K562/A02细胞内阿霉素的累积,并且这种增加具有pH值依赖性,随着酸化程度的加深细胞内阿霉素的累积也逐渐增加,阿霉素在细胞核内的分布也明显增多。随着细胞内pH的降低,K562/A02细胞中p38蛋白激酶磷酸化水平呈下降趋势,ERK蛋白激酶磷酸化水平呈上升趋势,JNK蛋白激酶磷酸化水平呈上升趋势。当应用ERK蛋白激酶抑制剂时,细胞酸化可诱导1938蛋白激酶磷酸化水平上升,对JNK蛋白激酶磷酸化水平未见影响。
结论:细胞酸化能够抑制K562/A02耐药细胞株的MDR1 mRNA转录,同时能够抑制P-gp的蛋白表达和功能,并能够增加阿霉素在耐药细胞中的累积及向细胞核内的分布。其信号转导机制可能是通过增强耐药细胞内ERK蛋白激酶磷酸化水平,间接抑制p38蛋白激酶的磷酸化水平,同时增强JNK蛋白激酶的磷酸化水平,最终下调P-gp的表达与功能。
Background:As the major obstacle of chemotherapy,multidrug resistance(MDR) leads to the chemoresistance and the decreased survival in leukemias.The tumor MDR is induced by one drug and results in the tumor resistance to other drugs and the failure of chemical therapy.The mechanism of MDR is complicate,and one of the most important reasons is the expression of P-gp.The P-gp is encoded by the MDR1 gene,and could transport the lipophilia drugs out of the tumor cells,which results in the decreased therapeutic effect and the redistribution of the anticancer drugs.With the development of P-gp modulators to the third generation,the regulation of pogp is still unsatisfactory.In recent years,it has been reported that cancer cells show a strong tendency towards an alkaline deviation of the entire homeostasis when they are resistant to therapeutic intervention.In order to clarify the internal correlation between pH_i and P-gp in MDR leukemia cells,we tested a potential role for intracellular acidification in reversing of MDR through P-gp regulation.
Objective:The aim of the study was to investigate the effect of intracellular acidification on the P-gp in K562/A02 cells,clarify the relation between intracellular acidification and the P-gp,and provide new strategy to reverse the MDR.
Method:Confocal laser microscope was used to determine the pH_i of the cells,and MTT assay was for determining the cytotoxicity of intracellular acidification on K562 and K562/A02 cells.By using real-time RT-PCR and western blot,the influences of intracellular acidification on P-gp expression at mRNA and protein levels were determined.Flow cytometry was applied to detect the influence of intracellular acidification on the activity of P-gp.Confocal laser microscope was also used to determine the accumulation and distribution of doxorubicin in K562 and K562/A02 cells. Western blot assay was used to detect the effect of intracellular acidification on the expression of P-gp,the phosphorylation level of p38 mitogen-activated protein kinase (MAPK),the extracellular signal regulated kinase(ERK) and the c-Jun amino-terminal kinase(JNK).
Results:The results indicated that intracellular acidification had no obvious cytotoxicity on K562 and K562/A02 cells,and it reduced the level of P-gp in a pH_i and time-dependent manner in K562/A02 cells.This occurred primarily at the mRNA level, which was revealed by real-time RT-PCR analysis.The P-gp expression was also down-regulated by intracellular acidification that revealed by western blot assay.The decrease of P-gp level was associated with a significant increased accumulation, decreased efflux of Rh123 and the increased accumulation of doxorubicin in the K562/A02 cells induced by the intracellular acidification.The phosphorylation level of p38 MAPK was decreased and the phosphorylation level of ERK and JNK was increased by the intracellular acidification.When the inhibitor of ERK was used,the phosphorylation level of p38 MAPK was increased significantly,and the JNK was not affected by the inhibitor.
Conclusions:The data indicated that the intracellular acidification could reverse the MDR of K562/A02 cells through down-regulation of P-gp activity and expression.The intracellular acidification might down-regulated the P-gp expression through MAPK signal transportation pathway.
引文
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