title: Asbestos induces nitric oxide synthesis in mesothelioma cells via Rho signaling inhibition.
abstract: We have observed that in three human malignant mesothelioma cell lines, crocidolite asbestos induced the activation of the transcription factor NF-kappaB and the synthesis of nitric oxide (NO) by inhibiting the RhoA signaling pathway. The incubation with crocidolite decreased the level of GTP-bound RhoA and the activity of Rho-dependent kinase, and induced the activation of Akt/PKB and IkBalpha kinase, leading to the nuclear translocation of NF-kappaB. The effects of crocidolite fibers on NF-kappaB activation and NO synthesis were mimicked by Y27632 (an inhibitor of the Rho-dependent kinases) and toxin B (an inhibitor of RhoA GTPase activity), while they were reverted by mevalonic acid, the product of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. Furthermore, crocidolite, similarly to mevastatin, inhibited the synthesis of cholesterol and ubiquinone and the prenylation of RhoA: these effects were prevented in the presence of mevalonic acid. This suggests that crocidolite fibers might inhibit the synthesis of isoprenoid molecules at the level of the HMGCoA reductase reaction or of an upstream step, thus impairing the prenylation and subsequent activation of RhoA. Akt can stimulate NO synthesis via a double mechanism: it can activate the inducible NO synthase via the NF-kappaB pathway and the endothelial NO synthase via a direct phosphorylation. Our results suggest that crocidolite increases the NO levels in mesothelioma cells by modulating both NO synthase isoforms.
authors.affiliation: Department of Genetics, Biology and Biochemistry, and Interdepartmental Center G. Scansetti for Studies on Asbestos and Other Toxic Particulates, Università di Torino, Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
authors.forename: Sara
authors.initials: S
authors.lastname: Orecchia
authors.forename: Francesca
authors.initials: F
authors.lastname: Silvagno
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Pescarmona
authors.forename: Pier Giacomo
authors.initials: PG
authors.lastname: Betta
authors.forename: Elena
authors.initials: E
authors.lastname: Gazzano
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Aldieri
authors.forename: Dario
authors.initials: D
authors.lastname: Ghigo
authors.forename: Amalia
authors.initials: A
authors.lastname: Bosia
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000577:Amides / Q000378:metabolism; D000818:Animals; D017638:Asbestos, Crocidolite / Q000378:metabolism*; D002417:Cattle; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000378:metabolism; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D008798:Mevalonic Acid / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology*; D013729:Terpenes / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016328:NF-kappa B; D011725:Pyridines; D013729:Terpenes; D017638:Asbestos, Crocidolite; C108830:Y 27632; C012258:mevastatin; D009569:Nitric Oxide; D008148:Lovastatin; D019001:Nitric Oxide Synthase; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D020741:rho GTP-Binding Proteins; D008798:Mevalonic Acid