Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells

Joseph C Lim, Katarzyna D Kania, Hasini Wijesuriya, Sangeeta Chawla, Jaswinder K Sethi, Lukasz Pulaski, Ignacio A Romero, Pierre O Couraud, Babette B Weksler, Stephen B Hladky, Margery A Barrand

Research output: Contribution to journalArticlepeer-review


This study investigates involvement of beta-catenin signalling in regulation of p-glycoprotein (p-gp) expression in endothelial cells derived from brain vasculature. Pharmacological interventions that enhance or that block beta-catenin signalling were applied to primary rat brain endothelial cells and to immortalized human brain endothelial cells, hCMEC/D3, nuclear translocation of beta-catenin being determined by immunocytochemistry and by western blot analysis to confirm effectiveness of the manipulations. Using the specific glycogen synthase kinase-3 (GSK-3) inhibitor 6-bromoindirubin-3'-oxime enhanced beta-catenin and increased p-gp expression including activating the MDR1 promoter. These increases were accompanied by increases in p-gp-mediated efflux capability as observed from alterations in intracellular fluorescent calcein accumulation detected by flow cytometry. Similar increases in p-gp expression were noted with other GSK-3 inhibitors, i.e. 1-azakenpaullone or LiCl. Application of Wnt agonist [2-amino-4-(3,4-(methylenedioxy) benzylamino)-6-(3-methoxyphenyl)pyrimidine] also enhanced beta-catenin and increased transcript and protein levels of p-gp. By contrast, down-regulating the pathway using Dickkopf-1 or quercetin decreased p-gp expression. Similar changes were observed with multidrug resistance protein 4 and breast cancer resistance protein, both known to be present at the blood-brain barrier. These results suggest that regulation of p-gp and other multidrug efflux transporters in brain vasculature can be influenced by beta-catenin signalling.
Original languageEnglish
Pages (from-to)1855-65
Number of pages11
JournalJournal of Neurochemistry
Issue number4
Publication statusPublished - Aug 2008


  • Animals
  • Blood-Brain Barrier
  • Brain
  • Cell Line, Transformed
  • Cells, Cultured
  • Down-Regulation
  • Endothelial Cells
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3
  • Humans
  • Indoles
  • Male
  • Oximes
  • P-Glycoprotein
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Up-Regulation
  • beta Catenin

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