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Asbestos Induces Nitric Oxide Synthesis in Mesothelioma Cells via Rho Signaling Inhibition

Department of Genetics, Biology and Biochemistry, and Interdepartmental Center "G. Scansetti" for Studies on Asbestos and Other Toxic Particulates, Università di Torino; Research Center on Experimental Medicine (CeRMS), Torino; and Pathology Unit, Department of Oncology, Azienda Sanitaria Ospedaliera, Alessandria, Italy

Correspondence and requests for reprints should be addressed to Dario Ghigo, Dipartimento di Genetica, Biologia e Biochimica (Sezione di Biochimica), Via Santena, 5/bis, 10126 Torino, Italy. E-mail: dario.ghigo{at}unito.it

We have observed that in three human malignant mesothelioma cell lines, crocidolite asbestos induced the activation of the transcription factor NF-B 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 IkB kinase, leading to the nuclear translocation of NF-B. The effects of crocidolite fibers on NF-B 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-B 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.

Key Words: crocidolite • mesothelioma • nitric oxide • RhoA • NF- • B

CLINICAL RELEVANCE In human malignant mesothelioma cells, crocidolite asbestos induces the activation of NF-B and the synthesis of nitric oxide by impairing the prenylation and subsequent activation of RhoA.