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The cross-talk between canonical and non-canonical Wnt-dependent pathways regulates P-glycoprotein expression in human blood-brain barrier cells
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Pinzon-Daza, Martha L.
Salaroglio, Iris C
Kopecka, Joanna
Garzòn, Ruth
Couraud, Pierre-Olivier
Ghigo, Dario
Riganti, Chiara
Fecha
2014
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Nature Publishing Group
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Abstract
In this work, we investigate if and how transducers of the 'canonical' Wnt pathway, i.e., Wnt/glycogen synthase kinase 3 (GSK3)/?-catenin, and transducers of the 'non-canonical' Wnt pathway, i.e., Wnt/RhoA/RhoA kinase (RhoAK), cooperate to control the expression of P-glycoprotein (Pgp) in blood-brain barrier (BBB) cells. By analyzing human primary brain microvascular endothelial cells constitutively activated for RhoA, silenced for RhoA or treated with the RhoAK inhibitor Y27632, we found that RhoAK phosphorylated and activated the protein tyrosine phosphatase 1B (PTP1B), which dephosphorylated tyrosine 216 of GSK3, decreasing the GSK3-mediated inhibition of ?-catenin. By contrast, the inhibition of RhoA/RhoAK axis prevented the activation of PTP1B, enhanced the GSK3-induced phosphorylation and ubiquitination of ?-catenin, and reduced the ?-catenin-driven transcription of Pgp. The RhoAK inhibition increased the delivery of Pgp substrates like doxorubicin across the BBB and improved the doxorubicin efficacy against glioblastoma cells co-cultured under a BBB monolayer. Our data demonstrate that in human BBB cells the expression of Pgp is controlled by a cross-talk between canonical and non-canonical Wnt pathways. The disruption of this cross-talk, e.g., by inhibiting RhoAK, downregulates Pgp and increases the delivery of Pgp substrates across the BBB. © 2014 ISCBFM.
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4 (1 aminoethyl) n (4 pyridyl)cyclohexanecarboxamide , tumor , Doxorubicin , Glycogen synthase kinase 3 , Multidrug resistance protein , Protein tyrosine phosphatase 1b , Rho kinase , Rhoa guanine nucleotide binding protein , Tyrosine , Wnt protein , Article , Blood brain barrier , Coculture , Concentration response , Controlled study , Dephosphorylation , Drug efficacy , Drug penetration , Drug transport , Enzyme activation , Enzyme inactivation , Enzyme inhibition , Enzyme phosphorylation , Gene silencing , Glioblastoma cell line , Human , Human cell , Microvascular endothelial cell , Priority journal , Protein expression , Protein protein interaction , Transcription regulation , Ubiquitination , Wnt signaling pathway , Amides , Beta catenin , Blood-brain barrier , Cell line , Cell survival , Coculture techniques , Doxorubicin , Endothelial cells , Glycogen synthase kinase 3 , Humans , P-glycoprotein , Permeability , Phosphorylation , Protein kinase inhibitors , Protein tyrosine phosphatase , Pyridines , Rho-associated kinases , Rhoa gtp-binding protein , Wnt signaling pathway , -catenin , Blood-brain barrier , Glycogen synthase kinase 3 , P-glycoprotein , Rhoa kinase , Wnt , ?
