Regulation of P-glycoprotein by miR-27a-3p at the Brain Endothelial Barrier.

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.

• Authors: Saba Hammad, Aloïse Mabondzo, Rifat Hamoudi, Rania Harati
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 111 Issue 5 Pg. 1470-1479 (05 2022) ISSN: 1520-6017 [Electronic] United States
• PMID: 34695419 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Catenins
• MicroRNAs

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Brain (metabolism)
• Catenins (metabolism)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Endothelium (metabolism)
• Humans
• MicroRNAs (genetics)