Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis

Abstract Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unab...

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Autores principales:	R. Reilly, M. S. Mroz, E. Dempsey, K. Wynne, S. J. Keely, E. F. McKone, C. Hiebel, C. Behl, J. A. Coppinger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/83f7d91151ee4471ab8b716bf6da8bf0
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spelling	oai:doaj.org-article:83f7d91151ee4471ab8b716bf6da8bf02021-12-02T11:40:59ZTargeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis10.1038/s41598-017-06588-z2045-2322https://doaj.org/article/83f7d91151ee4471ab8b716bf6da8bf02017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06588-zhttps://doaj.org/toc/2045-2322Abstract Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Using protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR. Our results demonstrated upregulated mTOR activity in ΔF508 CF bronchial epithelial (CFBE41o-) cells. Inhibition of the Phosphatidylinositol 3-kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathway with 6 different inhibitors demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CFBE41o- cells. We identified Bcl-2-associated athanogene 3 (BAG3), a regulator of autophagy and aggresome clearance to be a potential mechanistic target of MK-2206. These data further link the CFTR defect to autophagy deficiency and demonstrate the potential of the PI3K/Akt/mTOR pathway for therapeutic targeting in CF.R. ReillyM. S. MrozE. DempseyK. WynneS. J. KeelyE. F. McKoneC. HiebelC. BehlJ. A. CoppingerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q R. Reilly M. S. Mroz E. Dempsey K. Wynne S. J. Keely E. F. McKone C. Hiebel C. Behl J. A. Coppinger Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis
description	Abstract Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Using protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR. Our results demonstrated upregulated mTOR activity in ΔF508 CF bronchial epithelial (CFBE41o-) cells. Inhibition of the Phosphatidylinositol 3-kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathway with 6 different inhibitors demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CFBE41o- cells. We identified Bcl-2-associated athanogene 3 (BAG3), a regulator of autophagy and aggresome clearance to be a potential mechanistic target of MK-2206. These data further link the CFTR defect to autophagy deficiency and demonstrate the potential of the PI3K/Akt/mTOR pathway for therapeutic targeting in CF.
format	article
author	R. Reilly M. S. Mroz E. Dempsey K. Wynne S. J. Keely E. F. McKone C. Hiebel C. Behl J. A. Coppinger
author_facet	R. Reilly M. S. Mroz E. Dempsey K. Wynne S. J. Keely E. F. McKone C. Hiebel C. Behl J. A. Coppinger
author_sort	R. Reilly
title	Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis
title_short	Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis
title_full	Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis
title_fullStr	Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis
title_full_unstemmed	Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis
title_sort	targeting the pi3k/akt/mtor signalling pathway in cystic fibrosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/83f7d91151ee4471ab8b716bf6da8bf0
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Targeting the PI3K/Akt/mTOR signalling pathway in Cystic Fibrosis

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