Antioxidants Prevent the RhoA Inhibition Evoked by Crocidolite Asbestos in Human Mesothelial and Mesothelioma Cells

Abstract

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 unclear. We have previously observed that crocidolite in human MM (HMM) cells induces NF-kB activation and stimulates the synthesis of nitric oxide by inhibiting the RhoA signaling pathway. In primary human mesothelial cells (HMCs) and HMM cells exposed to crocidolite asbestos, coincubated or not with antioxidants, we evaluated cytotoxicity and oxidative stress induction (lipid peroxidation) and the effect of asbestos on the RhoA signaling pathway (RhoA GTP binding, Rho kinase activity, RhoA prenylation, hydroxy-3-methylglutharyl-CoA reductase activity). In this paper we show that the reactive oxygen species generated by the incubation of crocidolite with primary HMCs and three HMM cell lines mediate the inhibition of 3-hydroxy-3-methylglutharyl-CoA reductase (HMGCR). The coincubation of HMCs and HMM cells with crocidolite together with antioxidants, such as Tempol, Mn-porphyrin, and the association of superoxide dismutase and catalase, prevented the cytotoxicity and lipoperoxidation caused by crocidolite alone as well as the decrease of HMGCR activity and restored the RhoA/RhoA-dependent kinase activity and the RhoA prenylation. The same effect was observed when the oxidizing agent menadione was administrated to the cells in place of crocidolite. Such a mechanism could at least partly explain the effects exerted by crocidolite fibers in mesothelial cells.

Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function

“…Asbestos, which is the major environmental cause of malignant pleural mesothelioma, was shown to be involved in increased ROS levels within the pleura. It was subsequently suggested that asbestos-induced increased ROS levels was a major cause of the tumorigenesis of mesothelioma [ 35 ], and in vitro anti-oxidant treatment decreased invasive capacities of mesothelioma tumors [ 36 ]. Together with our results, these data suggest an interaction between BAP1 expression, ROS sensitivity and asbestos exposure [ 26 , 37 ].…”

Host–guest inclusion systems of Pt(IV)-bis(benzoato) anticancer drug candidates and cyclodextrins

“…All the compounds under investigation were tested on three primary MPM cancer cell lines, derived from the pleural effusion of previously untreated patients suffering from MPM, namely BR95 (epithelioid), MM98 (sarcomatoid) [34,35] and MG06 (mixed with epithelioid predominance), and on a cisplatin-resistant cell line called MM98R derived from wild type MM98 by exposure to sub-lethal concentrations of cisplatin for several months [36]. Human mesothelial cells (HMC) were established by gently scraping the peritoneum of the inner wall of uncomplicated congenital hernia sacs surgically excised from premature babies (Pediatric Surgery Unit).…”

RhoA and vigilin are candidates for immunohistochemical markers for epithelioid malignant mesothelioma

“…RhoA regulates non-small lung cancer cell migration, but RhoA-related signal cascades in mesothelioma cells are inhibited by crocidolite, a type of asbestos 23 . Crocidolite activates NF-κB and promotes the nitric oxide synthesis by inhibiting the RhoA signalling pathway 24 . Furthermore, RhoA signalling inhibits the migration of breast cancer cells by decreasing stress fibres 25 .…”