Crocidolite asbestos-induced signal pathway dysregulation in mesothelial cells

Our plain-English summary of Crocidolite asbestos-induced signal pathway dysregulation in mesothelial cells, by H. Wang, A. Gillis, C. Zhao, et al (Mutation Research, 2011).

The study

• Authors: H. Wang, A. Gillis, C. Zhao, E. Lee, J. Wu, F. Zhang, F. Ye, D.Y. Zhang
• Journal: Mutation Research
• Published: 2011;723(2):171-6
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant mesothelioma is a rare cancer caused by exposure to asbestos. Current therapies have limited efficacy and the prognosis is dismal. A better understanding of the underlying mechanism of asbestos-induced malignant transformation will help to identify molecular markers that can be used for diagnosis, prognosis or therapeutic targets.

Objectives: The objectives of this study are (1) to identify altered levels of proteins and phosphoproteins and (2) to establish the interactive network among those proteins in crocidolite-treated benign mesothelial cells and in malignant mesothelial cells.

Methods: Total cellular proteins were extracted from benign mesothelial cells, crocidolite-treated mesothelial cells and malignant mesothelial cells. The expression levels of 112 proteins and phosphoproteins were analyzed using a multiplex immunoblot-based assay followed by computational analysis (Protein Pathway Array).

Results: A total of 16 proteins/phosphoproteins (7 down-regulated and 9 up-regulated) were altered after exposure of benign mesothelial cells to crocidolite asbestos and the majority of them are involved in DNA damage repair and cell cycle regulation. In malignant mesothelial cells, 21 proteins/phosphoproteins (5 down-regulated and 16 up-regulated) were dysregulated and majority of them are involved in EGFR/ERK and PI3K/Akt pathways. Within the regulatory network affected by crocidolite, p53 and NF-κB complex are the most important regulators. There was substantial overlap in the regulatory networks between the asbestos-treated cells and malignant mesothelial cells.

Conclusions: Asbestos exposure has extensive effects on regulatory pathways and networks. These altered proteins may be used in the future to identify those with a high risk for developing malignant mesothelioma and as targets for preventing this deadly malignancy.

Copyright © 2011 Elsevier B.V. All rights reserved.

In plain English

This was a laboratory study of cells grown in culture, not a study of people. The authors used two cell lines. Met-5A is an immortalized normal mesothelial cell line. NCI-H28 was derived from an epithelioid malignant pleural mesothelioma. Met-5A cells were exposed to crocidolite asbestos fibers for 24 hours. The authors then measured 112 proteins and phosphoproteins with a multiplex immunoblot method, running each assay twice. After crocidolite exposure, 16 proteins changed by more than 1.5-fold (7 lower and 9 higher). The authors described most of these as involved in the DNA damage response and cell cycle control. The malignant cells differed from untreated normal cells in 21 proteins: 5 were higher, 12 were lower, and 4 were not detected in the malignant cells. Nine proteins changed in both comparisons. Three of them rose after asbestos exposure but were lower in the malignant cells. A computer network analysis identified p53 and the NF-kappaB complex as central hubs in both settings. The authors concluded that asbestos caused a wide range of pathway changes and that these proteins may in future help identify people at high risk of malignant mesothelioma.

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: Laboratory (in vitro) cell-culture experiment, using a multiplex immunoblot protein assay (Protein Pathway Array) followed by computer-based pathway and network analysis
• Who was studied: Two human cell lines from the American Type Culture Collection: Met-5A, an immortalized normal mesothelial cell line, and NCI-H28, derived from an epithelioid malignant pleural mesothelioma. No human subjects were studied.
• Exposure: UICC crocidolite asbestos fibers applied to the non-malignant (Met-5A) cells for 24 hours. The dose was 0 (control) or a dose printed as '10 g/cm2'; the unit's prefix symbol appears to have been lost in the text.
• Main results:
  • In normal mesothelial cells exposed to crocidolite, 16 proteins/phosphoproteins changed by more than 1.5-fold compared with untreated cells: 7 decreased and 9 increased.
  • The authors described most of the crocidolite-altered proteins as involved in the DNA damage response, especially control of cell cycle progression.
  • In the crocidolite-treated normal cells, phosphorylated p53 decreased and unphosphorylated p53 increased (Table 1: p-p53 (Ser392) -2.01-fold; p53 2.75-fold).
  • Malignant NCI-H28 cells differed from untreated normal Met-5A cells in 21 proteins/phosphoproteins (more than 1.5-fold): 5 higher and 12 lower in the malignant cells.
  • Four proteins were not detected at all in the malignant cells: beta-catenin, p-p53 (Ser392), p16 and p14.
  • Nine proteins changed both in the crocidolite-treated cells and in the malignant cells. Three of them (p-c-Jun (Ser73), p53 and beta-catenin) were increased in the asbestos-treated cells but decreased in the malignant cells.
  • In the pathway analysis of crocidolite effects, the p53 pathway had the highest log p-value (14.2), followed by arylhydrocarbon receptor signaling (8.8) and PI3K/Akt signaling (7.2).
  • In the network built for the malignant cells, p53 and the NF-kappaB complex were the most connected hubs, as they were in the crocidolite network. NF-kappaB was not itself measured by the authors' assay.
• The authors' conclusion: The authors concluded that asbestos caused a wide range of regulatory pathway changes and that TP53 and NF-kappaB may play critical roles in the development of malignant mesothelioma. They suggested the altered proteins may be used to identify people at high risk and as targets for prevention.
• Limitations the authors state:
  • The authors noted that some of their results disagree with earlier reports. They suggested the differences may come from different antibodies, cell lines and methods.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Crocidolite, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Crocidolite, Mesothelial Cells, Malignant Mesothelioma, Prognosis, Malignant Transformation, EGFR, Asbestos Exposure.

Related studies

• Apoptosis induced by crocidolite asbestos in human lung epithelial cells involves inactivation of Akt and MAPK pathways — A. Baldys, P. Pande, et al. (2007)
• An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury — A. Shukla, T.F. Barrett, et al. (2011)
• Mineral fibre toxicity: expression of retinoblastoma (Rb) and phospho-retinoblastoma (pRb) protein in alveolar epithelial and mesothelial cell lines exposed to fluoro-edenite fibres — G. Musumeci, V. Cardile, et al. (2011)
• Iron-related toxicity of single-walled carbon nanotubes and crocidolite fibres in human mesothelial cells investigated by Synchrotron XRF microscopy — F. Cammisuli, S. Giordani, et al. (2018)
• Crocidolite asbestos inhibits pentose phosphate oxidative pathway and glucose 6-phosphate dehydrogenase activity in human lung epithelial cells — C. Riganti, E. Aldieri, et al. (2002)
• Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters — B. Kroczynska, R. Cutrone, et al. (2006)

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