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

Oncotarget
Ye ZhangYunpeng Liu

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.

References

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Citations

Jan 16, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Song ZhangSaijun Mo
May 27, 2017·Oxidative Medicine and Cellular Longevity·Shengqi WangZhiyu Wang
May 21, 2016·Oncotarget·Fengyun WangHua Zhu
May 22, 2020·Frontiers in Oncology·Xiuming LiuLingyun Zhang
Apr 7, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Jun DengJian Ping Xiong
Oct 23, 2018·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Margaret E TomeThomas P Davis
May 4, 2021·Frontiers in Pharmacology·Yuanqi LiuChunfang Zhang
Oct 1, 2021·Frontiers in Oncology·Jin-Hai TianLi-Bin Wang

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Methods Mentioned

BETA
ubiquitination
fluorescence microscopy
co-immunoprecipitation
transfection
xenografts
surgical resection
immunoprecipitation
electrophoresis
flow cytometry
proximity ligation assay

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