Hammad, Saba;
Mabondzo, Aloïse;
Hamoudi, Rifat;
Harati, Rania;
(2022)
Regulation of P-glycoprotein by miR-27a-3p at the Brain Endothelial Barrier.
Journal of Pharmaceutical Sciences
, 111
(5)
pp. 1470-1479.
10.1016/j.xphs.2021.10.021.
Preview |
Text (Article)
Hamoudi_miR-27a-3p Brain.doc.pdf Download (423kB) | Preview |
Preview |
Text (Figures)
Hamoudi_miR-27a-3p Brain Figures File.doc.pdf Download (1MB) | Preview |
Abstract
Multi-drug resistance P-glycoprotein (P-gp/MDR1) is one of the most clinically relevant ABC transporters, highly enriched at the blood-brain barrier (BBB) with a broad substrate spectrum including therapeutic drugs and metabolic waste products. Altered P-gp transport function has been implicated in multi-drug resistance and in the pathogenesis and progression of neurological diseases. Recent studies have shown that P-gp expression is modulated by micro-RNAs in peripheral organs. Particularly, miR-27a-3p has been shown to play a critical role in the regulation of P-gp in multi-drug resistant cancer cells. In brain disorders, altered levels of miR-27a-3p were reported in several diseases associated with alterations in P-gp expression at the BBB. However, effect of altered miR-27a-3p expression on P-gp expression at the BBB remains to be determined. In this study, we investigated the role of miR-27a-3p in the regulation of P-gp expression and activity at the brain endothelium. Levels of miR-27a-3p were modulated by mimic and inhibitor transfection in an in-vitro model of human brain endothelial hCMEC/D3 cells. Effect of miR-27a-3p modulation on P-gp expression and activity was examined and the underlying regulatory mechanisms explored. Our results showed that transfection of hCMEC/D3 cells with miR-27a-3p mimic induces expression and activity of P-gp while miR-27a-3p inhibition exerted opposite effects. Mechanistic studies revealed that miR-27a-3p regulates P-gp by mediating Glycogen Synthase Kinase 3 Beta (GSK3ß) inhibition and activating Wnt/ß-catenin signaling. These findings shed light on miR-27a-3p/GSK3ß/ß-catenin as a novel axis that could be exploited to modulate P-gp efflux activity at the brain endothelium and help improving CNS diseases treatment or brain protection.
| Type: | Article |
|---|---|
| Title: | Regulation of P-glycoprotein by miR-27a-3p at the Brain Endothelial Barrier |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.xphs.2021.10.021 |
| Publisher version: | https://doi.org/10.1016/j.xphs.2021.10.021 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | miR-27a-3p, p-glycoprotein, GSK3ss, Wnt, ss-catenin, Brain endothelium, Blood-brain barrier |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10154641 |
Archive Staff Only
 |
View Item |
