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

Ye Zhang1, Xiujuan Qu1, Yuee Teng1

  • 1Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.

Oncotarget
|March 20, 2015
PubMed

Insights

This study reveals how P-glycoprotein (P-gp) moves into caveolae, driving multidrug resistance (MDR) in cancer. A protein called Cbl-b reverses this by degrading c-Src, improving patient survival.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • P-glycoprotein (P-gp) transport function depends on its localization to caveolae, specialized lipid rafts.
  • Disruption of caveolae impairs P-gp transport, but the regulatory molecules are unknown.

Purpose of the Study:

  • To elucidate the molecular mechanism regulating P-gp translocation into caveolae.
  • To identify novel targets for overcoming multidrug resistance (MDR) in cancer.

Main Methods:

  • Investigated c-Src and Caveolin-1 interactions in P-gp translocation using gastric and breast cancer cell lines (SGC7901/Adr, MCF-7/Adr).
  • Analyzed the role of Cbl-b in a negative feedback loop involving c-Src ubiquitination and degradation.
  • Correlated Cbl-b expression with patient survival in anthracycline-treated breast cancer patients with P-gp positive tumors.

Main Results:

  • c-Src-dependent Caveolin-1 phosphorylation promotes P-gp translocation into caveolae, enhancing MDR.
  • Cbl-b nuclear-to-cytoplasmic translocation inhibits P-gp localization by degrading c-Src, reversing MDR.
  • Increased Cbl-b expression positively correlates with survival in P-gp positive breast cancer patients.

Conclusions:

  • Identified a novel c-Src/Caveolin-1 pathway regulating P-gp function and MDR.
  • Demonstrated a Cbl-b-mediated negative feedback loop that reverses MDR.
  • Cbl-b serves as a potential prognostic biomarker and therapeutic target in P-gp mediated MDR cancers.
Keywords:
Cbl-bP-gpcaveolaemultiple drug-resistant

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