Asbestos redirects nitric oxide signaling through rapid catalytic conversion to nitrite

Asbestos exposure is strongly associated with the development of malignant mesothelioma, yet the mechanistic! basis of this observation has not been resolved. Carcinogenic transformation or tumor progression mediated by asbestos may be related to the generation of free radical species and perturbation of cell signaling and transcription factors. We report here that exposure of human mesothelioma or lung carcinoma cells to nitric oxide (NO) in the presence of crocidolite asbestos resulted in a marked decrease in intracellular nitrosation and diminished NO-induced post-translational modifications of tumor-associated proteins (hypoxia-inducible factor-1 alpha and p53). Crocidolite rapidly scavenged NO with concomitant conversion to nitrite (NO2-). Crocidolite also catalyzed the nitration of cellular proteins in the presence of NO2- and hydrogen peroxide. Nitrated protein adducts are a prominent feature of asbestos-induced lung injury. These data highlight the ability of asbestos to induce phenotypic cellular changes through two processes: (a) by directly reducing bioactive NO levels and preventing its subsequent interaction with target molecules and (b) by increasing oxidative damage and protein modifications through NO2 production and 3-nitrotyrosine formation.