Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers
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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
Yunpeng Liu, e-mail: [email protected]
Xiujuan Qu, e-mail: [email protected]
Keywords: Cbl-b, P-gp, Caveolae, Multiple Drug-resistant
Received: November 30, 2014 Accepted: January 29, 2015 Published: February 17, 2015
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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