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

• Published in: Scientific reports Vol. 7; no. 1; pp. 7642 - 13
• Main Authors: Reilly, R., Mroz, M. S., Dempsey, E., Wynne, K., Keely, S. J., McKone, E. F., Hiebel, C., Behl, C., Coppinger, J. A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-08-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 101/58; 631/80/86; 631/80/86/2364; 96/106; 96/63; 96/95; AKT protein; Autophagy; Bcl-2 protein; Bioinformatics; Cell Line; Children; Chromatography, Liquid; Clonal deletion; Computational Biology - methods; Conductance; Cystic fibrosis; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Endoplasmic reticulum; Gene Ontology; Humanities and Social Sciences; Humans; Mammals; Mass Spectrometry; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mechanistic Target of Rapamycin Complex 2 - metabolism; Models, Biological; multidisciplinary; Multiprotein Complexes - metabolism; Neoplasm Staging; Phagocytosis; Phenylalanine; Phosphatidylinositol 3-Kinase - metabolism; Protein Binding; Protein Interaction Mapping; Protein Interaction Maps; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; RNA, Small Interfering - genetics; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Therapeutic targets; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-06588-z

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.