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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

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...

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Detalles Bibliográficos
Autores Principales: Pinzon-Daza, Martha L., Salaroglio, Iris C, Kopecka, Joanna, Garzòn, Ruth, Couraud, Pierre-Olivier, Ghigo, Dario, Riganti, Chiara
Formato: Artículo (Article)
Lenguaje:Inglés (English)
Publicado: Nature Publishing Group 2014
Materias:
4 (1 aminoethyl) n (4 pyridyl)cyclohexanecarboxamide
Beta catenin
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
Blood-brain barrier
Cell survival
Coculture techniques
Endothelial cells
Humans
P-glycoprotein
Permeability
Phosphorylation
Protein kinase inhibitors
Pyridines
Rho-associated kinases
Rhoa gtp-binding protein
-catenin
Rhoa kinase
Wnt
?
non-receptor type 1
tumor
Cell line
Protein tyrosine phosphatase
Acceso en línea:https://repository.urosario.edu.co/handle/10336/22282
https://doi.org/10.1038/jcbfm.2014.100
Descripción
Sumario: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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