American Journal of Respiratory Cell and Molecular Biology. 2011 Jan 21. [Epub ahead of print] [Link]
Aldieri E, Riganti C, Silvagno F, Orecchia S, Betta PG, Doublier S, Gazzano E, Polimeni M, Bosia A, Ghigo D.
Genetics, Biology and Biochemistry, University of Turino, Turino, Italy; University of Torino, Interdepartmental Center "G. Scansetti" for Studies on Asbestos and Other Toxic Particulates, Torino, Italy; University of Torino, Research Center on Experimental Medicine (CeRMS), Torino, Italy.
Rationale: Asbestos is a naturally occurring fibrous silicate, whose inhalation is highly related to the risk of developing malignant mesothelioma (MM), and crocidolite is one of its most oncogenic types. The mechanism by which asbestos may cause MM is still unclear. We have previously observed that crocidolite in human MM cells (HMM) induces NF-kB activation and stimulates the synthesis of nitric oxide by inhibiting the RhoA signaling pathway.
Methods: In primary human mesothelial cells (HMC) and HMM cells exposed to crocidolite asbestos, co-incubated or not with antioxidants, we evaluated both cytotoxicity and oxidative stress induction (lipid peroxidation), then the effect of asbestos on the RhoA signaling pathway (RhoA GTP binding, Rho kinase activity, RhoA prenylation, hydroxy-3-methylglutharyl-CoA reductase activity). Results. In this paper we show that the reactive oxygen species generated by the incubation of crocidolite with both primary HMC and three human MM cell lines mediate the inhibition of 3-hydroxy-3-methylglutharyl-CoA reductase (HMGCR). Indeed the co-incubation of HMC and HMM cells with crocidolite together with antioxidants, such as Tempol, Mn-porphyrin and the association of superoxide dismutase and catalase, completely prevented the cytotoxicity and lipoperoxidation caused by crocidolite alone, as well as the decrease of HMGCR activity, and restored the RhoA/ROCK activity and the RhoA prenylation. The same effect was observed when the oxidizing agent menadione was administrated to the cells in place of crocidolite.
Conclusions: Such a mechanism could at least partly explain the effects exerted by crocidolite fibers in mesothelial cells.