Frizzled fissure to improve central nervous system drug delivery?
| Autor: | Lester R. Drewes |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Frizzled
Beta-catenin Cell Survival Pyridines Biology Blood–brain barrier Permeability Glycogen Synthase Kinase 3 Cell Line Tumor medicine Humans ATP Binding Cassette Transporter Subfamily B Member 1 Phosphorylation Protein Kinase Inhibitors Wnt Signaling Pathway beta Catenin P-glycoprotein Protein Tyrosine Phosphatase Non-Receptor Type 1 rho-Associated Kinases Glycogen Synthase Kinase 3 beta Feature Article Wnt signaling pathway LRP6 Endothelial Cells LRP5 Amides Coculture Techniques Cell biology medicine.anatomical_structure Neurology Blood-Brain Barrier Doxorubicin Drug delivery biology.protein Neurology (clinical) Cardiology and Cardiovascular Medicine rhoA GTP-Binding Protein Feature Article Commentary |
| 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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