Apoptosis induced by crocidolite asbestos in human lung epithelial cells involves inactivation of Akt and MAPK pathways

Our plain-English summary of Apoptosis induced by crocidolite asbestos in human lung epithelial cells involves inactivation of Akt and MAPK pathways, by A. Baldys, P. Pande, T. Mosleh, et al (Apoptosis, 2007).

The study

• Authors: A. Baldys, P. Pande, T. Mosleh, S.H. Park, A.E. Aust
• Journal: Apoptosis
• Published: 2007;12(2):433-47
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Exposure of human lung epithelial (A549) cells to asbestos fibers causes apoptosis, which is largely attributed to release of iron and generation of reactive oxygen species (ROS) within the cells. To mimic the highly oxidative environment generated by asbestos exposure in the absence of the actual fibers, we used two chemicals; buthione sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis and ferric ammonium citrate (FAC), a source of iron. Here, we report that exposure of A549 cells to crocidolite asbestos led to a significant time-dependent inactivation of signaling proteins, i.e. Akt and all mitogen-activated protein kinases (MAPKs) (p38, ERK1/2 and SAPK/JNK), and subsequently to apoptosis. Unlike crocidolite treatment, the use of BSO and FAC, independently or combined, did not change the phosphorylation status of proteins, nor did it induce apoptosis. Taken together, our results presented herein point to the possibility that crocidolite-induced apoptosis of human lung epithelial cells is not a mere consequence of generation of oxidants but also requires inactivation of major cell growth and differentiation pathways.

In plain English

This was a laboratory study of A549 human lung epithelial cells, not of people. The authors exposed cells to crocidolite asbestos (6 micrograms per square centimetre) for 0.25 to 24 hours. To imitate crocidolite's iron release and glutathione loss, they treated cells for 24 hours with two chemicals, BSO and ferric ammonium citrate (FAC), alone or together. Crocidolite triggered markers of apoptosis (programmed cell death), including cleavage of caspase-9, caspase-3 and PARP. The chemicals did not induce apoptosis; FAC alone caused some procaspase-3 cleavage, with no increase in caspase-3 activity. Crocidolite also caused a time-dependent loss of phosphorylation, an activating signal, in Akt and all three MAPK pathways, which govern cell growth and survival. It lowered protein levels of Akt, SAPK/JNK and p38 but not ERK1/2. BSO and FAC altered some signals, but the authors called those changes random and smaller. The authors concluded their results point to the possibility that crocidolite-induced apoptosis is not only due to oxidants but also requires inactivation of major growth pathways. They noted that differing sites of oxidant production might explain the contrast.

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 cell culture experiment (in vitro), using Western blotting and a caspase activity assay
• Who was studied: A549 human lung epithelial cell line with characteristics of alveolar epithelial type II cells (no human subjects); results shown are representative of 3 separate experiments
• Exposure: crocidolite asbestos at 6 µg/cm2 (27% iron by weight; mean length 10 µm, mean width 0.27 µm) for 0.25 to 24 h; comparison treatments of 4.23 µM BSO (glutathione synthesis inhibitor) and 4.75 mM ferric ammonium citrate (iron source), alone or combined, for 24 h
• Main results:
  • In A549 cells, crocidolite caused time-dependent cleavage of caspase-9 and caspase-3 (markers of apoptosis) over 0.25 to 24 h
  • After 24 h, crocidolite increased caspase-3 activity, and only crocidolite (not BSO or FAC, alone or combined) led to PARP cleavage
  • FAC alone caused some procaspase-3 cleavage, but the 24-h BSO and FAC treatments, alone or combined, did not induce caspase-3 activity; the authors concluded these treatments did not mimic crocidolite in inducing apoptosis
  • Crocidolite caused a time-dependent reduction of most total cellular phospho-tyrosine and phospho-threonine below untreated control cells
  • Crocidolite caused time-dependent inactivation of the MAPK pathways (SAPK/JNK, p38, ERK1/2) and the PI3K/Akt pathway
  • In the PI3K/Akt pathway, crocidolite blocked phosphorylation of all proteins examined except PTEN, which stayed phosphorylated
  • In crocidolite-treated cells, protein levels of Akt, SAPK/JNK and p38 decreased, but ERK1/2 levels did not
  • BSO and FAC altered phosphorylation of some MAPKs, but the authors described these changes as random and smaller than with crocidolite
• The authors' conclusion: The authors concluded that their results point to the possibility that crocidolite-induced apoptosis of human lung epithelial cells is not only a consequence of oxidant generation but also requires inactivation of major cell growth and differentiation pathways
• Limitations the authors state:
  • The authors noted that the differences between crocidolite and BSO/FAC might be due to oxidants being produced in different parts of the cell (mitochondria versus cytosol)
  • The authors stated that a role for phosphatases could not be ruled out, although crocidolite did not activate the two they examined (unpublished observations)

Topics

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

Medical terms in this study, explained in our Lexicon: Apoptosis, Crocidolite, Reactive Oxygen Species (ROS), Asbestos Exposure, Glutathione (GSH), A549 Cells.

Related studies

• Role of extracellular signal-regulated protein kinases in apoptosis by asbestos and H2O2 — L.A. Jiménez, C. Zanella, et al. (1997)
• Raw single-wall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-kappaB, and Akt in normal and malignant human mesothelial cells — M. Pacurari, X.J. Yin, et al. (2008)
• P53 mediates amosite asbestos-induced alveolar epithelial cell mitochondria-regulated apoptosis — V. Panduri, S. Surapureddi, et al. (2006)
• Asbestos-induced activation of cell signaling pathways in human bronchial epithelial cells — X. Wang, J.M. Samet, et al. (2006)
• Distinct autophagy-apoptosis related pathways activated by Multi-walled (NM 400) and Single-walled carbon nanotubes (NIST-SRM2483) in human bronchial epithelial (16HBE14o-) cells — M. Ghosh, S. Murugadoss, et al. (2020)
• The c-Jun N-terminal kinase signaling pathway mediates chrysotile asbestos-induced alveolar epithelial cell apoptosis — P. Li, T. Liu, et al. (2015)

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