Functional enhancement of CFTR expression by mitomycin C

Cystic fibrosis is caused by mutations in the CFTR gene. The most common of these mutations, DeltaF508, results in a protein that is not trafficked to the apical plasma membrane but instead is retained and degraded in the endoplasmic reticulum (ER) by the 26S proteosome. However, this protein is functional upon plasma membrane expression. It has been theoretically estimated that even a modest ( approximately 10%) increase in CFTR-associated chloride conductance can be beneficial in a clinical setting. Thus, understanding basic CFTR biogenesis is important, and identification of prototypical compounds that can increase CFTR expression and trafficking is potentially useful in the development of novel therapeutic strategies to treat cystic fibrosis. We report that mitomycin C (MMC) elicits such a response by increasing CFTR mRNA and protein expression in T-84 and HT-29 cells at very low, non-cytotoxic, pharmacologically relevant concentrations (0.1 microM) leading to enhanced chloride secretion. Thus, MMC may be a useful compound for understanding CFTR regulation and biogenesis.