Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells.
Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells.
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Rack1介导P-糖蛋白与Anxa2的相互作用并调节多药耐药乳腺癌细胞的迁移和侵袭
DOI：
10.3390/ijms17101718
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发表时间：
2016-10-13
影响因子：
5.6
通讯作者：
Niu R
中科院分区：
文献类型：
--
作者：
Yang Y;Wu N;Wang Z;Zhang F;Tian R;Ji W;Ren X;Niu R
多药耐药的出现往往与肿瘤的快速复发和转移有关。P-糖蛋白（P-gp）是一种多药外排转运蛋白，能增强耐药细胞的侵袭能力。已有研究表明P-gp可能通过蛋白质间相互作用发挥其促肿瘤作用。这些相互作用与细胞内信号传导的激活有关。我们以前发现，P-gp结合到Anxa 2，并通过调节Anxa 2磷酸化促进多药耐药（MDR）乳腺癌细胞的侵袭力。然而，确切的机制仍不清楚。本研究采用免疫共沉淀结合液相色谱-串联质谱的相互作用组学方法筛选P-gp结合蛋白。我们确定Rack 1为一种新的P-gp结合蛋白。Rack 1基因的敲除可显著抑制MDR癌细胞的增殖和侵袭。机制研究表明Rack 1作为支架蛋白介导P-gp与Anxa 2和Src的结合。我们发现Rack 1调节P-gp活性，这是阿霉素诱导的P-gp介导的Anxa 2和Erk 1/2磷酸化所必需的。总体而言，本研究的发现增加了新的见解，以了解P-gp促进MDR癌细胞迁移和侵袭的机制。
The emergence of multidrug resistance is always associated with more rapid tumor recurrence and metastasis. P-glycoprotein (P-gp), which is a well-known multidrug-efflux transporter, confers enhanced invasion ability in drug-resistant cells. Previous studies have shown that P-gp probably exerts its tumor-promoting function via protein-protein interaction. These interactions were implicated in the activation of intracellular signal transduction. We previously showed that P-gp binds to Anxa2 and promotes the invasiveness of multidrug-resistant (MDR) breast cancer cells through regulation of Anxa2 phosphorylation. However, the accurate mechanism remains unclear. In the present study, a co-immunoprecipitation coupled with liquid chromatography tandem mass spectrometry-based interactomic approach was performed to screen P-gp binding proteins. We identified Rack1 as a novel P-gp binding protein. Knockdown of Rack1 significantly inhibited proliferation and invasion of MDR cancer cells. Mechanistic studies demonstrated that Rack1 functioned as a scaffold protein that mediated the binding of P-gp to Anxa2 and Src. We showed that Rack1 regulated P-gp activity, which was necessary for adriamycin-induced P-gp-mediated phosphorylation of Anxa2 and Erk1/2. Overall, the findings in this study augment novel insights to the understanding of the mechanism employed by P-gp for promoting migration and invasion of MDR cancer cells.
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DOI：
10.1042/bj20101010
发表时间：
2010-11-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Bird RJ;Baillie GS;Yarwood SJ
通讯作者：
Yarwood SJ
影响因子：
4.8
作者：
Hoffmann, Andreas-Claudius;Wild, Peter;Hartmann, Arndt
通讯作者：
Hartmann, Arndt
RACK1通过激活RhoA/Rho激酶通路促进乳腺癌迁移/转移
影响因子：
3.8
作者：
Cao, Xi-Xi;Xu, Jing-Da;Liu, Xiu-Ping
通讯作者：
Liu, Xiu-Ping
影响因子：
8.8
作者：
Hao, J.;Chen, H.;Li, Y.
通讯作者：
Li, Y.
影响因子：
8
作者：
Chang, BY;Harte, RA;Cartwright, CA
通讯作者：
Cartwright, CA