Oncotarget

Research Papers:

Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers

Ye Zhang, Xiujuan Qu, Yuee Teng, Zhi Li, Ling Xu, Jing Liu, Yanju Ma, Yibo Fan, Ce Li, Shizhou Liu, Zhenning Wang, Xuejun Hu, Jingdong Zhang and Yunpeng Liu _

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Oncotarget. 2015; 6:6737-6748. https://doi.org/10.18632/oncotarget.3253

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Abstract

Ye Zhang1, Xiujuan Qu1, Yuee Teng1, Zhi Li1, Ling Xu1, Jing Liu1, Yanju Ma1, Yibo Fan1, Ce Li1, Shizhou Liu1, Zhenning Wang2, Xuejun Hu3, Jingdong Zhang1, Yunpeng Liu1

1Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China

2Department of Surgical Oncology and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China

3Department of Medical Respiratory, the First Hospital of China Medical University, Shenyang 110001, China

Correspondence to:

Yunpeng Liu, e-mail: ypliu@mail.cmu.edu.cn

Xiujuan Qu, e-mail: qu_xiujuan@hotmail.com

Keywords: Cbl-b, P-gp, Caveolae, Multiple Drug-resistant

Received: November 30, 2014     Accepted: January 29, 2015     Published: February 17, 2015

ABSTRACT

The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. In the present study, we showed that c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Our findings identified a new regulatory mechanism of P-gp transport function in multiple drug-resistant gastric and breast cancers.


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