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Int. J. Mol. Sci. 2016, 17(10), 1718; doi:10.3390/ijms17101718

Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells

1,2,3,4,†
,
2,3,5,6,†
,
1,2,3,4
,
1,2,3,4
,
1,2,3,4
,
1,2,3,4
,
2,3,5,6,* and 1,2,3,4,*
1
Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
2
Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
3
Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
4
Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China
5
Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
6
Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 17 August 2016 / Revised: 18 September 2016 / Accepted: 7 October 2016 / Published: 13 October 2016
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Abstract

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. View Full-Text
Keywords: P-glycoprotein; Rack1; Anxa2; MDR; invasion; breast cancer; Src P-glycoprotein; Rack1; Anxa2; MDR; invasion; breast cancer; Src
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Yang, Y.; Wu, N.; Wang, Z.; Zhang, F.; Tian, R.; Ji, W.; Ren, X.; Niu, R. Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells. Int. J. Mol. Sci. 2016, 17, 1718.

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