Regulation of P-glycoprotein by miR-27a-3p at the Brain Endothelial Barrier
| Autor: | Saba Hammad, Rania Harati, Aloïse Mabondzo, Rifat Hamoudi |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
biology
Chemistry Wnt signaling pathway Brain Pharmaceutical Science Catenins Transporter Transfection Human brain Blood–brain barrier Drug Resistance Multiple Cell biology MicroRNAs medicine.anatomical_structure Drug Resistance Neoplasm medicine biology.protein Humans ATP Binding Cassette Transporter Subfamily B Member 1 Endothelium Efflux GSK3B P-glycoprotein |
| Zdroj: | Journal of Pharmaceutical Sciences. 111:1470-1479 |
| ISSN: | 0022-3549 |
| Popis: | 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 (GSK3s) inhibition and activating Wnt/s-catenin signaling. These findings shed light on miR-27a-3p/GSK3s/s-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. |
| Databáze: | OpenAIRE |
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