Activation of NF-κB by asbestos through EGF-R signalling in mesothelial cells is important in cell survival

Asbestos fibres up-regulate the expression of the epidermal growth factor receptor (EGF-R) in mesothelial cells, the progenitor cells of mesothelioma. Exposure of mesothelial cells to asbestos leads initially to cell toxicity, followed by the selection of a clone of cells which proliferate. Asbestos exposure is associated with the activation of nuclear factor-κB (NF-κB), a transcription factor important in the regulation of genes intrinsic to inflammation and lung defences. The studies here have examined whether there is a relationship between EGF-R and NF-κB in mesothelial cells exposed to asbestos fibres and the impact of NF-κB activation on mesothelial cell survival. Using gel mobility shift assays, we have shown that crocidolite asbestos increases the DNA binding activity of NF-κB in MET5A cells, a human mesothelial cell line. Pre-treatment with antioxidants, such as curcumin or N -acetylcysteine, or the selective EGF-R tyrosine kinase inhibitor, PKI166, inhibited the nuclear translocation of NF-κB mediated by crocidolite. Crocidolite in combination with PKI166 increased the cellular toxicity of crocidolite compared with that observed with crocidolite alone. Our results indicate that the induction of NF-κB by crocidolite is via a signalling pathway linked to EGF-R, and that this survival signal protects mesothelial cells against the cellular toxicity of crocidolite. Modulation of these signalling pathways may be important in the development of novel therapeutic strategies for both the chemoprevention and treatment of malignant mesothelioma.