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

R Reilly1, M S Mroz2, E Dempsey3

  • 1Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

Scientific Reports
|August 11, 2017
PubMed

Insights

Targeting the PI3K/Akt/mTOR pathway can restore autophagy and improve cystic fibrosis transmembrane conductance regulator (CFTR) expression in cystic fibrosis (CF) cells. This offers a promising therapeutic strategy for CF treatment.

Area of Science:

  • Cell Biology
  • Molecular Medicine
  • Genetics

Background:

  • Cystic fibrosis (CF) is primarily caused by the ΔF508 CFTR mutation, leading to protein misfolding and ER retention.
  • Developing treatments to improve ΔF508 CFTR trafficking from the endoplasmic reticulum (ER) is crucial for CF therapy.

Purpose of the Study:

  • To investigate the association between mammalian target of rapamycin (mTOR) signaling and ΔF508 CFTR.
  • To evaluate the therapeutic potential of inhibiting the PI3K/Akt/mTOR pathway for CF.

Main Methods:

  • Protein interaction profiling and bioinformatics analysis to identify signaling pathways linked to ΔF508 CFTR.
  • Utilizing six different PI3K/Akt/mTOR inhibitors on ΔF508 CF bronchial epithelial cells (CFBE41o-).
  • Investigating the role of autophagy and Bcl-2-associated athanogene 3 (BAG3) in the therapeutic mechanism.

Main Results:

  • Upregulated mTOR activity was observed in ΔF508 CFBE41o- cells.
  • Inhibition of the PI3K/Akt/mTOR pathway increased CFTR stability and expression.
  • The inhibitor MK-2206 restored autophagy and potentially targeted BAG3, improving cellular function.

Conclusions:

  • The PI3K/Akt/mTOR pathway is implicated in CFTR trafficking defects.
  • Targeting this pathway, particularly with autophagy restoration, presents a viable therapeutic avenue for cystic fibrosis.

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