Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 34, Issue 8, Pages 1258-1269Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2014.100
Keywords
blood-brain barrier; beta-catenin; glycogen synthase kinase 3; P-glycoprotein; RhoA kinase; Wnt
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Funding
- Compagnia di San Paolo, Italy (Neuroscience Program) [2008.1136]
- Italian Association for Cancer Research (AIRC) [MFAG 11475]
- Italian Ministry of University and Research (Future in Research FIRB) [RBFR125OQ1]
- ERACOL Erasmus Mundus fellowship by EU
- 'Mario and Valeria Rindi' fellowship by Italian Foundation for Cancer Research (FIRC)
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In this work, we investigate if and how transducers of the 'canonical' Wnt pathway, i.e., Wnt/glycogen synthase kinase 3 (GSK3)/beta-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 beta-catenin. By contrast, the inhibition of RhoA/RhoAK axis prevented the activation of PTP1B, enhanced the GSK3-induced phosphorylation and ubiquitination of beta-catenin, and reduced the beta-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.
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