Asbestos redirects nitric oxide signaling through rapid catalytic conversion to nitrite

Our plain-English summary of Asbestos redirects nitric oxide signaling through rapid catalytic conversion to nitrite, by D.D. Thomas, M.G. Espey, D.A. Pociask, et al (Cancer Research, 2006).

The study

• Authors: D.D. Thomas, M.G. Espey, D.A. Pociask, L.A. Ridnour, S. Donzelli, D.A. Wink
• Journal: Cancer Research
• Published: 2006;66(24):11600-4
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos exposure is strongly associated with the development of malignant mesothelioma, yet the mechanistic basis of this observation has not been resolved. Carcinogenic transformation or tumor progression mediated by asbestos may be related to the generation of free radical species and perturbation of cell signaling and transcription factors. We report here that exposure of human mesothelioma or lung carcinoma cells to nitric oxide (NO) in the presence of crocidolite asbestos resulted in a marked decrease in intracellular nitrosation and diminished NO-induced posttranslational modifications of tumor-associated proteins (hypoxia-inducible factor-1alpha and p53). Crocidolite rapidly scavenged NO with concomitant conversion to nitrite (NO(2)(-)). Crocidolite also catalyzed the nitration of cellular proteins in the presence of NO(2)(-) and hydrogen peroxide. Nitrated protein adducts are a prominent feature of asbestos-induced lung injury. These data highlight the ability of asbestos to induce phenotypic cellular changes through two processes: (a) by directly reducing bioactive NO levels and preventing its subsequent interaction with target molecules and (b) by increasing oxidative damage and protein modifications through NO(2) production and 3-nitrotyrosine formation.

In plain English

This laboratory study used chemical assays and cultured human cell lines (JMN and Mesto-211H mesothelioma, A549 lung carcinoma, MCF-7 breast adenocarcinoma) to examine how crocidolite asbestos interacts with nitric oxide (NO). The crocidolite contained 27 percent (plus or minus 4) iron. In buffer, crocidolite sharply accelerated the loss of NO, which then followed first-order kinetics, with parallel stoichiometric accumulation of nitrite; hydrogen peroxide and ascorbate accelerated it further and the metal chelator DTPA reduced it. In the cell-free albumin assay, crocidolite with nitrite and hydrogen peroxide produced substantial 3-nitrotyrosine, whereas glass wool fibres of similar size and concentration gave no detectable 3-nitrotyrosine; crocidolite also catalysed 3-nitrotyrosine formation in JMN, Mesto-211H and A549 cells when nitrite and hydrogen peroxide were present. In A549 cells HIF-1alpha accumulated with as little as 25 micromol/L Sper/NO, while p53 phospho-serine-15 required 50 to 100 micromol/L. Crocidolite present during NO exposure suppressed the HIF-1alpha response in JMN cells and both responses in MCF-7 cells; in DAF-2-loaded JMN cells fluorescence reached only 30 percent of that without crocidolite. The authors concluded asbestos can redirect NO signalling and increase protein nitration.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: in vitro laboratory study combining cell-free chemical kinetics experiments with human cancer cell line experiments
• Who was studied: Human cell lines: JMN and Mesto-211H mesothelioma, A549 lung cancer, and MCF-7 breast adenocarcinoma cells, plus cell-free solutions of human serum albumin
• Exposure: Crocidolite asbestos fibres (sheared and sonicated, about 3 to 5 micrometres long, 0.22 micrometres diameter, iron content 27 percent plus or minus 4), used with nitric oxide (from the donor Sper/NO), nitrite, hydrogen peroxide, ascorbate and ATP; glass wool fibres of similar size served as negative controls
• Main results:
  • Crocidolite greatly accelerated the disappearance of NO in solution, changing the kinetics to first order; hydrogen peroxide and ascorbate accelerated it further and the chelator DTPA reduced it
  • Loss of NO in the presence of crocidolite was matched by immediate, stoichiometric accumulation of nitrite
  • In the cell-free assay, human serum albumin incubated with nitrite, hydrogen peroxide and crocidolite formed substantial 3-nitrotyrosine; with glass wool fibres of similar size and concentration none was detected
  • Crocidolite-catalysed 3-nitrotyrosine formation was also shown in two mesothelioma cell lines (JMN, Mesto-211H) and a lung carcinoma line (A549), dose-dependently and only when nitrite and hydrogen peroxide were present; DTPA reduced it
  • In A549 lung cells, HIF-1alpha accumulated at Sper/NO of 25 micromol/L or more, while p53 phospho-serine-15 required 50 to 100 micromol/L Sper/NO
  • In JMN cells, crocidolite present during NO exposure markedly suppressed the NO-induced increases in HIF-1alpha
  • In MCF-7 cells treated with 50 micromol/L Sper/NO, both the HIF-1alpha and p53 responses were abated in the presence of crocidolite
  • In DAF-2-loaded JMN cells exposed to 5 micromol/L Sper/NO, crocidolite reduced intracellular fluorescence yield to 30 percent of that seen without crocidolite
  • JMN mesothelioma cells treated 16 hours with crocidolite at 1, 10 and 100 micrograms per square centimetre with or without 100 micromol/L nitrite and hydrogen peroxide showed viability decreases of 5.8, 6.5 and 17.17 percent (plus or minus 2, 2.3 and 5) versus asbestos-free controls
• The authors' conclusion: The authors concluded that the chemical and physical make-up of asbestos is sufficient to influence cellular phenotype, by consuming NO to nitrite, forming protein nitrotyrosine adducts non-enzymatically and disrupting NO-mediated signalling, and they suggested this may relate to the etiology of malignant mesothelioma

Topics

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Malignant Mesothelioma, Carcinogenic, Mesothelioma, Carcinoma, Crocidolite, Hypoxia.

Related studies

• Mechanisms of asbestos-induced nitric oxide production by rat alveolar macrophages in inhalation and in vitro models — T.R. Quinlan, K.A. BeruBe, et al. (1998)
• Intrapleural interleukin-2 induces nitric oxide production in pleural effusions from malignant mesothelioma: a possible mechanism of interleukin-2-mediated cytotoxicity? — C. Porta, V. Rizzo, et al. (2002)
• The role of nitric oxide in pleural disease — O.S. Kotsiou, K.I. Gourgoulianis, et al. (2021)
• Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis — H. Ohshima, H. Bartsch (1994)
• Participation of nitric oxide and iron in the oxidation of DNA in asbestos-treated human lung epithelial cells — C.C. Chao, S.H. Park, et al. (1996)
• Increased alveolar nitric oxide concentration and high levels of leukotriene B(4) and 8-isoprostane in exhaled breath condensate in patients with asbestosis — H. Lehtonen, P. Oksa, et al. (2007)

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