Rescue of F508-CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) by Curcumin: Involvement of the Keratin 18 Network
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS(2006)
摘要
The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, Delta F508, causes retention of Delta F508-CFTR in the endoplasmic reticulum and leads to the absence of CFTR Cl- channels in the plasma membrane. Delta F508- CFTR retains some Cl- channel activity so increased expression of Delta F508-CFTR in the plasma membrane can restore Cl- secretion deficiency. Recently, curcumin was shown to rescue Delta F508-CFTR localization and function. In our previous work, the keratin 18 (K18) network was implicated in Delta F508-CFTR trafficking. Here, we hypothesized that curcumin could restore a functional Delta F508-CFTR to the plasma membrane acting via the K18 network. First, we analyzed the effects of curcumin on the localization of Delta F508-CFTR in different cell lines ( HeLa cells stably transfected with wild-type CFTR or Delta F508- CFTR, CALU-3 cells, or cystic fibrosis pancreatic epithelial cells CFPAC-1) and found that it was significantly delocalized toward the plasma membrane in Delta F508-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 Delta F508-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 Delta F508-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.
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