Rescue of DeltaF508-CFTR (cystic fibrosis transmembrane conductance regulator) by curcumin: involvement of the keratin 18 network

J Pharmacol Exp Ther. 2006 May;317(2):500-5. doi: 10.1124/jpet.105.097667. Epub 2006 Jan 19.


The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, DeltaF508, causes retention of DeltaF508-CFTR in the endoplasmic reticulum and leads to the absence of CFTR Cl(-) channels in the plasma membrane. DeltaF508-CFTR retains some Cl(-) channel activity so increased expression of DeltaF508-CFTR in the plasma membrane can restore Cl(-) secretion deficiency. Recently, curcumin was shown to rescue DeltaF508-CFTR localization and function. In our previous work, the keratin 18 (K18) network was implicated in DeltaF508-CFTR trafficking. Here, we hypothesized that curcumin could restore a functional DeltaF508-CFTR to the plasma membrane acting via the K18 network. First, we analyzed the effects of curcumin on the localization of DeltaF508-CFTR in different cell lines (HeLa cells stably transfected with wild-type CFTR or DeltaF508-CFTR, CALU-3 cells, or cystic fibrosis pancreatic epithelial cells CFPAC-1) and found that it was significantly delocalized toward the plasma membrane in DeltaF508-CFTR-expressing cells. We also performed a functional assay for the CFTR chloride channel in CFPAC-1 cells treated or not with curcumin and detected an increase in a cAMP-dependent chloride efflux in treated DeltaF508-CFTR-expressing cells. The K18 network then was analyzed by immunocytochemistry and immunoblot exclusively in curcumin-treated or untreated CFPAC-1 cells because of their endogenic DeltaF508-CFTR expression. After curcumin treatment, we observed a remodeling of the K18 network and a significant increase in K18 Ser52 phosphorylation, a site directly implicated in the reorganization of intermediate filaments. With these results, we propose that K18 as a new therapeutic target and curcumin, and/or its analogs, might be considered as potential therapeutic agents for cystic fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Curcumin / pharmacology*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Immunoblotting
  • Keratin-18
  • Keratins / metabolism*
  • Mutation
  • Time Factors


  • KRT18 protein, human
  • Keratin-18
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Keratins
  • Curcumin