Targeting autophagy as a novel strategy for facilitating the therapeutic action of potentiators on ?F508 cystic fibrosis transmembrane conductance regulator.

ABSTRACT: Channel activators (potentiators) of cystic fibrosis (CF) transmembrane conductance regulator (CFTR), can be used for the treatment of the small subset of CF patients that carry plasma membrane-resident CFTR mutants. However, approximately 90% of CF patients carry the misfolded ?F508-CFTR and are poorly responsive to potentiators, because ?F508-CFTR is intrinsically unstable at the plasma membrane (PM) even if rescued by pharmacological correctors. We have demonstrated that human and mouse CF airways are autophagy deficient due to functional sequestration of BECN1 and that the tissue transglutaminase-2 inhibitor, cystamine, or antioxidants restore BECN1-dependent autophagy and reduce SQSTM1/p62 levels, thus favoring ?F508-CFTR trafficking to the epithelial surface. Here, we investigated whether these treatments could facilitate the beneficial action of potentiators on ?F508-CFTR homozygous airways. Cystamine or the superoxide dismutase (SOD)/catalase-mimetic EUK-134 stabilized ?F508-CFTR at the plasma membrane of airway epithelial cells and sustained the expression of CFTR at the epithelial surface well beyond drug withdrawal, overexpressing BECN1 and depleting SQSTM1. This facilitates the beneficial action of potentiators in controlling inflammation in ex vivo ?F508-CFTR homozygous human nasal biopsies and in vivo in mouse ?F508-CFTR lungs. Direct depletion of Sqstm1 by shRNAs in vivo in ?F508-CFTR mice synergized with potentiators in sustaining surface CFTR expression and suppressing inflammation. Cystamine pre-treatment restored ?F508-CFTR response to the CFTR potentiators genistein, Vrx-532 or Vrx-770 in freshly isolated brushed nasal epithelial cells from ?F508-CFTR homozygous patients. These findings delineate a novel therapeutic strategy for the treatment of CF patients with the ?F508-CFTR mutation in which patients are first treated with cystamine and subsequently pulsed with CFTR potentiators.

SUBMITTER: Luciani A 

PROVIDER: S-EPMC3494594 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature