Activated ERM Protein Plays a Critical Role in Drug Resistance of MOLT4 Cells Induced by CCL25
Activated ERM Protein Plays a Critical Role in Drug Resistance of MOLT4 Cells Induced by CCL25
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激活的ERM蛋白在CCL25诱导的MOLT4细胞耐药中起关键作用
DOI：
10.1371/journal.pone.0052384
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发表时间：
2013-01-09
期刊：
影响因子：
3.7
通讯作者：
Zhang, Qiuping
中科院分区：
文献类型：
--
作者：
Zhang, Li;Xiao, Ruijing;Zhang, Qiuping
我们先前已经证明，CCR 9/CCL 25信号通路通过诱导T-ALL细胞系MOLT 4中具有极化分布的ERM蛋白的激活在人类急性T淋巴细胞白血病（T-ALL）的耐药性中起重要作用。然而，活化的ERM蛋白在由CCL 25诱导的MOLT 4细胞的耐药性中的作用机制仍然没有表征。我们研究了CCR 9/CCL 25在高表达CCR 9的T-ALL细胞中引发耐药性的机制。我们的研究结果表明：1）CCL 25处理后，P-gp的功能增加; 2）P-gp在CCL 25处理的细胞中与p-ERM和F-actin共定位和共免疫沉淀; 3）ERM-shRNA赋予药物敏感性，与CCL 25处理后释放的ERM与P-gp和F-actin的相互作用一致。提示P-gp通过p-ERM与F-actin细胞骨架结合在CCR 9/CCL 25诱导的T-ALL细胞多药耐药中起关键作用。旨在抑制P-gp-F-actin细胞骨架结合的策略可能有助于提高T-ALL的治疗效率。
We have previously demonstrated that the CCR9/CCL25 signaling pathway plays an important role in drug resistance in human acute T-lymphocytic leukemia (T-ALL) by inducing activation of ERM protein with polarized distribution in T-ALL cell line MOLT4. However, the mechanism of action of the activated ERM protein in the drug resistance of MOLT4 cells induced by CCL25 remains uncharacterized. Here we investigated the mechanism of CCR9/CCL25-initiated drug resistance in CCR9-high-expressing T-ALL cells. Our results showed that 1) the function of P-gp was increased after treatment with CCL25; 2) P-gp colocalized and co-immunoprecipitated with p-ERM and F-actin in CCL25 treated cells; and 3) ERM-shRNA conferred drug sensitivity coincident with release of ERM interactions with P-gp and F-actin after treatment with CCL25. These data suggest it is pivotal that P-gp associate with the F-actin cytoskeleton through p-ERM in CCR9/CCL25 induced multidrug resistance of T-ALL cells. Strategies aimed at inhibiting P-gp-F-actin cytoskeleton association may be helpful in increasing the efficiency of therapies in T-ALL.