Altered Biogenesis of ΔF508-CFTR Following Treatment with Doxorubicin

Cystic fibrosis (CF) is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common of these mutations is deletion of a phenylalanine residue at position 508 (ΔF508), which accounts for ~70% of all CF alleles. This mutation interferes with the biogenesis and maturation of ΔF508-CFTR to the plasma membrane. However, ΔF508-CFTR can partially function upon proper localization. Thus, pharmacological correction of ΔF508-CFTR maturation holds promise in CF therapy. Our previous studies indicate that a single non-cytotoxic dose of the anthracycline doxorubicin (Dox) significantly increase ΔF508-CFTR-associated chloride secretion in MDCK cells by increasing the expression of this protein at the apical plasma membrane. We report here that Dox alters the biogenesis of ΔF508-CFTR. Treatment with Dox increases the resistance of ΔF508-CFTR to trypsin digestion, possibly by expediting protein folding. Further, treatment with Dox reduces the amount of polyubiquitinated ΔF508-CFTR in cells and prolongs the half-life of this protein. Concomitantly, treatment with Dox decreases the association of ΔF508-CFTR with HSP70 but does not alter the expression of major HSP70 family members. Based on these results, we propose that Dox expedites the folding and maturation of ΔF508-CFTR by acting as a pharmacological chaperone, which consequently promotes the functional expression of this protein in MDCK cells. D ow nl oa de d by : 54 .1 91 .4 0. 80 5 /4 /2 01 7 4: 48 :5 3 A M