DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response

Casalone, Elisabetta; Allione, Alessandra; Viberti, Clara; Pardini, Barbara; Guarrera, Simonetta; Betti, Marta; Dianzani, Irma; Aldieri, Elisabetta; Matullo, Giuseppe

doi:10.1007/s00204-018-2179-y

Cited by 18 publications

(17 citation statements)

References 46 publications

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“…CA9 indeed contributes to the migration and invasion of tumor cells through enhancing MMP14-mediated collagen degradation in breast cancer cells [39]; CA9 overexpression can increase metastatic potential through Rho-GTPase-related epithelial-mesenchymal transition in a cervical cancer cell line [40]; CA9 overexpression is associated with a reduced Th1 response and worse overall survival in metastatic melanoma and basal-like breast cancer [41]. In the present study, we used human MM cells to identify the molecular events surrounding CA9 from the viewpoint of iron metabolism, considering a recent report that crocidolite or chrysotile exposure upregulates CA9 expression in an immortalized mesothelial cell line, MeT-5A [42]. An intimate association of iron metabolism with hypoxia and redox regulation via CA9 was for the first time revealed.…”

Section: Introductionmentioning

confidence: 99%

Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia

et al. 2019

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Hypoxia and acidity provide microenvironment for selection under evolutionary pressure and proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present in all life kingdoms, equilibrating the reactions among CO2, bicarbonate and H+. CA9, a membrane-associated α-CA, has been a drug target for various cancers. Whereas iron is essential not only for cancer cells but also for all the lives on earth, little is known on the association among hypoxia, iron metabolism, extracellular acidity and redox regulation. Malignant mesothelioma (MM), an aggressive tumor with poor prognosis, is an intriguing model in that asbestos-associated pathogenesis includes excess iron environment during carcinogenesis. Re-analysis of rat asbestos-induced MM model revealed an inverse association between high CA9 expression and survival. Here we used human MMs to identify the molecular events surrounding CA9 from the viewpoint of iron metabolism. CA9 expression was significantly higher in MM cells than in MeT-5A mesothelial cells, which was further amplified under hypoxia (1%O2) with increased catalytic Fe(II). CA9 suppression by inhibitors (S4 and U104) decreased viability and migration of MM cells, accompanied by overexpression of TFRC, IREB1/2 and FPN1(SLC40A1) and by downregulation of FTH/FTL. This expressional pattern was similar to that of erastin-induced ferroptosis in the same cells. Furthermore, we observed mitochondrial fission and enhanced autophagy with increased catalytic Fe(II) in both mitochondria and lysosomes after CA9 inhibition, accompanied by increased peroxides, mitochondrial O2− and lipid peroxidation. The eventual cell death was significantly inhibited by deferoxamine, ferrostatin-1 and Z-VAD-FMK, suggesting a mixed cell death of ferroptosis and apoptosis. Therefore, CA9 plays a role in equilibrating among hypoxia, iron metabolism and redox regulation in MM cells.

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Section: Introductionmentioning

confidence: 99%

Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia

et al. 2019

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“…To the best of our knowledge, no regulatory agency or scientific body has ever proposed a cancer potency factor for asbestos by combining different cancer types (EPA 2020b, p. 151) We urge the Agency to be cautious about applying any variation of the linearized multistage (LMS) model to estimate the risks of low dose exposure for short chrysotile fibers. Currently, the specific mechanism of carcinogenesis from exposure to chrysotile asbestos is not firmly established, and an association between exposure and a recurrent signature for pleural mesothelioma has not been identified (Bueno et al 2016;Hylebos et al 2016;Casalone et al 2018;Hmeljak et al 2018;Lorenzini 2021). There is also evidence that both pleural mesothelioma and lung cancer can undergo epigenetic modifications (i.e.…”

Section: Epa's Chrysotile Risk Evaluation Has Already Influenced the Litigationmentioning

confidence: 99%

A critical review of the 2020 EPA risk assessment for chrysotile and its many shortcomings

Paustenbach

Brew

Ligas

et al. 2021

Critical Reviews in Toxicology

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From 2018 to 2020, the United States Environmental Protection Agency (EPA) performed a risk evaluation of chrysotile asbestos to evaluate the hazards of asbestos-containing products (e.g. encapsulated products), including brakes and gaskets, allegedly currently sold in the United States. During the public review period, the EPA received more than 100 letters commenting on the proposed risk evaluation. The Science Advisory Committee on Chemicals (SACC), which peer reviewed the document, asked approximately 100 questions of the EPA that they expected to be addressed prior to publication of the final version of the risk assessment on 30 December 2020. After careful analysis, the authors of this manuscript found many significant scientific shortcomings in both the EPA's draft and final versions of the chrysotile risk evaluation. First, the EPA provided insufficient evidence regarding the current number of chrysotile-containing brakes and gaskets being sold in the United States, which influences the need for regulatory oversight. Second, the Agency did not give adequate consideration to the more than 200 air samples detailed in the published literature of auto mechanics who changed brakes in the 1970-1989 era. Third, the Agency did not consider more than 15 epidemiology studies indicating that exposures to encapsulated chrysotile asbestos in brakes and gaskets, which were generally in commerce from approximately 1950-1985, did not increase the incidence of any asbestos-related disease. Fourth, the concern about chrysotile asbestos being a mesothelioma hazard was based on populations in two facilities where mixed exposure to chrysotile and commercial amphibole asbestos (amosite and crocidolite) occurred. All 8 cases of pleural cancer and mesothelioma in the examined populations arose in facilities where amphiboles were present. It was therefore inappropriate to rely on these cohorts to predict the health risks of exposure to short fiber chrysotile, especially of those fibers filled with phenolic resins. Fifth, the suggested inhalation unit risk (IUR) for chrysotile asbestos was far too high since it was not markedly different than for amosite, despite the fact that the amphiboles are a far more potent carcinogen. Sixth, the approach to low dose modeling was not the most appropriate one in several respects, but, without question, it should have accounted for the background rate of mesothelioma in the general population. Just one month after this assessment was published, the National Academies of Science notified the EPA that the Agency's systematic review process was flawed. The result of the EPA's chrysotile asbestos risk evaluation is that society can expect dozens of years of scientifically unwarranted litigation. Due to an aging population and because some fraction of the population is naturally predisposed to mesothelioma given the presence of various genetic mutations in DNA repair mechanisms (e.g. BAP1 and others), the vast majority of mesotheliomas in the post-2035 era are expected to be spontaneous and unrelat...

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“…Asbestos fibers are associated with the development of both malignant (lung cancers, mesothelioma) and non-malignant (asbestosis) diseases [15]. Noticeably, while asbestos is known to cause genotoxicity through DNA breaks and oxidative damage, no association between asbestos exposure and a precise and recurrent MPM mutational profile could be established, thus failing to identify an asbestos-associated mutational signature at the origin of MPM [8,11,16].…”

Section: Asbestos-mediated Epigenetic Changesmentioning

confidence: 99%

Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations

Lorenzini

Ciarrocchi

Torricelli

2021

JCM

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Malignant pleural mesothelioma (MPM) is a clinical emergency of our time. Being strongly associated with asbestos exposure, incidence of this cancer is ramping up these days in many industrialized countries and it will soon start to increase in many developing areas where the use of this silicate derivate is still largely in use. Deficiency of reliable markers for the early identification of these tumors and the limited efficacy of the currently available therapeutic options are the basis of the impressive mortality rate of MPM. These shortcomings reflect the very poor information available about the molecular basis of this disease. Results of the recently released deep profiling studies point to the epigenome as a central element in MPM development and progression. First, MPM is characterized by a low mutational burden and a highly peculiar set of mutations that hits almost exclusively epigenetic keepers or proteins controlling chromatin organization and function. Furthermore, asbestos does not seem to be associated with a distinctive mutational signature, while the precise mapping of epigenetic changes caused by this carcinogen has been defined, suggesting that alterations in epigenetic features are the driving force in the development of this disease. Last but not least, consistent evidence also indicates that, in the setting of MPM, chromatin rewiring and epigenetic alterations of cancer cells heavily condition the microenvironment, including the immune response. In this review we aim to point to the relevance of the epigenome in MPM and to highlight the dependency of this tumor on chromatin organization and function. We also intend to discuss the opportunity of targeting these mechanisms as potential therapeutic options for MPM.

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DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response

Cited by 18 publications

References 46 publications

Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia

Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia

A critical review of the 2020 EPA risk assessment for chrysotile and its many shortcomings

Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations

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