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; Yunpeng Liu

doi:10.18632/oncotarget.3253

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

Oncotarget. 2015 Mar 30;6(9):6737-48. doi: 10.18632/oncotarget.3253.

Authors

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

Affiliations

¹ Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
² Department of Surgical Oncology and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China.
³ Department of Medical Respiratory, the First Hospital of China Medical University, Shenyang 110001, China.

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.

Keywords: Cbl-b; P-gp; caveolae; multiple drug-resistant.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / metabolism
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Adult
Animals
Antibiotics, Antineoplastic / therapeutic use
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / mortality
Breast Neoplasms / pathology
Caveolae / drug effects
Caveolae / metabolism*
Caveolin 1 / genetics
Caveolin 1 / metabolism
Chemotherapy, Adjuvant
Doxorubicin / therapeutic use
Drug Resistance, Multiple*
Drug Resistance, Neoplasm*
Female
Humans
MCF-7 Cells
Male
Mice, Nude
Phosphorylation
Protein Transport
Proteolysis
Proto-Oncogene Proteins c-cbl / genetics
Proto-Oncogene Proteins c-cbl / metabolism*
Proto-Oncogene Proteins pp60(c-src) / metabolism
RNA Interference
Stomach Neoplasms / drug therapy
Stomach Neoplasms / genetics
Stomach Neoplasms / metabolism*
Stomach Neoplasms / pathology
Time Factors
Transfection
Treatment Outcome
Ubiquitination
Xenograft Model Antitumor Assays

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Adaptor Proteins, Signal Transducing
Antibiotics, Antineoplastic
CAV1 protein, human
Caveolin 1
Doxorubicin
CBLB protein, human
Proto-Oncogene Proteins c-cbl
Proto-Oncogene Proteins pp60(c-src)