Cell signalling pathways in mesothelial cells treated with mineral fibres

Malignant mesothelioma (MM) is a major health problem as it is an invariably fatal disease resulting from occupational exposure to asbestos. The long latency period of this disease means that death rates will continue to rise for 10-20 years before improved exposure regulations take effect.;The studies described here were designed to explore mechanisms by which asbestos exposure elicits this malignancy. Cell signalling events germane to malignant transformation were investigated in rat (4/4 RM4) and human (MET5A) mesothelial cells in vitro following exposure to asbestos. The activation state of the MAPK family and Akt were probed, because these pathways are pivotal in determining death or survival of the cell. The results suggest that extracellular signal regulated protein kinase (ERK), p38 and Akt are activated by asbestos exposure. For the former two, at least, this activation depended on oxidative stress. A selective inhibitor of EGFR tyrosine kinase, PKI166, inhibited asbestos-mediated Akt and ERK activation. Asbestos-mediated Akt activation was also inhibited by LY294002, an inhibitor of phosphatidylinositol 3-kinase (P13K). The effect of events triggered by asbestos downstream of these kinases, on the transcription factors activator protein (AP) -1 and nuclear factor-kB (NF-kB) were investigated. Pharmacological inhibition of either the ERK pathway by UO126 or the p38 pathway by SB203580 ameliorated crocidolite-induced AP-1 activation. Inhibition of the Akt pathway by LY294002 or PKI166 reduced crocidolite-induced NF-kB translocation. The same panel of inhibitors were used to investigate the role of these pathways in defined endpoints characteristic of asbestos exposure i.e. cell death and survival/proliferation. In both cell lines the p38 pathway was involved in cell death and the Akt pathway in survival. In 4/4 RM4 cells activation of the ERK pathway also induced cell death. In contrast, in MET5A cells ERK appeared to be involved in survival.