The Cross-Talk between Canonical and Non-Canonical Wnt-Dependent Pathways Regulates P-Glycoprotein Expression in Human Blood–Brain Barrier Cells
| Autor: | Pierre-Olivier Couraud, Dario Antonio Ghigo, Joanna Kopecka, Chiara Riganti, Iris Chiara Salaroglio, Ruth Garzón, Martha L. Pinzon-Daza |
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| Rok vydání: | 2014 |
| Předmět: |
RHOA
Pyridines Endothelial cells Enzyme activation catenin Cell survival GSK-3 Rho kinase Phosphorylation Priority journal Blood-brain barrier P-glycoprotein Enzyme phosphorylation Kinase Wnt signaling pathway Drug transport Enzyme inactivation Gene silencing Transcription regulation RhoA kinase Cell biology Enzyme inhibition Neurology 4 (1 aminoethyl) n (4 pyridyl)cyclohexanecarboxamide Blood brain barrier Microvascular endothelial cell Cardiology and Cardiovascular Medicine Human tumor Protein tyrosine phosphatase 1b Beta-catenin Protein kinase inhibitors Beta catenin non-receptor type 1 Biology Concentration response Rho-associated kinases Protein tyrosine phosphatase Article Permeability Dephosphorylation Wnt Glioblastoma cell line Rhoa kinase Humans ? GSK3B Ubiquitination Multidrug resistance protein Wnt protein Amides Coculture Drug efficacy Glycogen synthase kinase 3 Human cell Doxorubicin Drug penetration Rhoa gtp-binding protein Protein protein interaction Cancer research biology.protein Tyrosine Protein expression Coculture techniques Neurology (clinical) Cell line Rhoa guanine nucleotide binding protein Controlled study |
| Zdroj: | Repositorio EdocUR-U. Rosario Universidad del Rosario instacron:Universidad del Rosario |
| ISSN: | 1559-7016 0271-678X |
| DOI: | 10.1038/jcbfm.2014.100 |
| Popis: | In this work, we investigate if and how transducers of the ‘canonical’ Wnt pathway, i.e., Wnt/glycogen synthase kinase 3 (GSK3)/β-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 β-catenin. By contrast, the inhibition of RhoA/RhoAK axis prevented the activation of PTP1B, enhanced the GSK3-induced phosphorylation and ubiquitination of β-catenin, and reduced the β-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. |
| Databáze: | OpenAIRE |
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