title: Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers.
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.
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Ye
authors: Y
authors: Zhang
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Xiujuan
authors: X
authors: Qu
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Yuee
authors: Y
authors: Teng
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Zhi
authors: Z
authors: Li
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Ling
authors: L
authors: Xu
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Jing
authors: J
authors: Liu
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Yanju
authors: Y
authors: Ma
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Yibo
authors: Y
authors: Fan
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Ce
authors: C
authors: Li
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Shizhou
authors: S
authors: Liu
authors: Department of Surgical Oncology and General Surgery, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Zhenning
authors: Z
authors: Wang
authors: Department of Medical Respiratory, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Xuejun
authors: X
authors: Hu
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Jingdong
authors: J
authors: Zhang
authors: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
authors: Yunpeng
authors: Y
authors: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008819:Mice, Nude; D010766:Phosphorylation; D021381:Protein Transport; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; C495540:CAV1 protein, human; D051242:Caveolin 1; D004317:Doxorubicin; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D016392:Proto-Oncogene Proteins pp60(c-src)
keywords: Cbl-b; P-gp; caveolae; multiple drug-resistant