In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 714-714
Kurzfassung:
Background 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. Methods Immunofluorescence microscopy and proximity ligation assays were used to analyze the translocation of P-gp into caveolae. Nude mice (n = 7 mice per group) were injected with SGC7901/Adr vector, SGC7901/Adr + Cbl-b cells and/or Dox and tumor growth was assessed. Immunoprecipitation and western blotting were used to examine the effects of Cbl-b mediated ubiquitination and degradation of c-Src. Immunochemistry was performed on primary tumor specimens from breast cancer patients (n = 319) to determine the relationship of Cbl-b with overall survival. Results c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance (MDR) 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. Conclusions Our findings reveal a new regulatory mechanism of P-gp transport function. Citation Format: Ye Zhang, Xiujuan Qu, Yuee Teng, Ling Xu, Jing Liu, Zhi Li, Xuejun Hu, Yunpeng Liu. Cbl-b Inhibits p-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 714. doi:10.1158/1538-7445.AM2015-714
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-714
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2015
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
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