Role of iron in inactivation of epidermal growth factor receptor after asbestos treatment of human lung and pleural target cells

Our plain-English summary of Role of iron in inactivation of epidermal growth factor receptor after asbestos treatment of human lung and pleural target cells, by A. Baldys, A.E. Aust (American Journal of Respiratory Cell and Molecular Biology, 2005).

The study

• Authors: A. Baldys, A.E. Aust
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2005;32(5):436-42
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Although the mechanism by which asbestos causes cancer remains unknown, iron associated with asbestos is thought to play a role in the pathogenic effects of fibers. Here, we examined the effects of asbestos on the epidermal growth factor receptor (EGFR) in human lung epithelial (A549) cells, human pleural mesothelial (MET5A) cells, and normal human small airway epithelial (SAEC) cells. Treatment of A549, MET5A, and SAEC cells with asbestos caused a significant reduction of EGFR tyrosine phosphorylation. This was both time- (15 min to 24 h) and concentration-dependent (1.5, 3, and 6 mug/cm(2)) in A549 cells. Also, treatment with 6 mug/cm(2) crocidolite for 24 h diminished the phosphorylation levels of human EGFR 2 (HER2). Exposure of A549 cells to 6 mug/cm(2) crocidolite for 3-24 h resulted in no detectable Y1045 phosphorylation and no apparent degradation of the EGFR. Inhibition of fiber endocytosis resulted in a considerable inhibition of EGFR dephosphorylation. Removal of iron from asbestos by desferrioxamine B or phytic acid inhibited asbestos-induced decreases in EGFR phosphorylation. The effects of crocidolite, amosite, and chrysotile on the EGFR phosphorylation state appeared to be directly related to the amount of iron mobilized from these fibers. These results strongly suggest that iron plays an important role in asbestos-induced inactivation of EGFR.

In plain English

This laboratory study used human cells, not people. The authors exposed A549 lung epithelial cells (from a lung carcinoma), MET5A pleural mesothelial cells, and normal small airway epithelial cells to asbestos. They measured the epidermal growth factor receptor (EGFR), a cell-surface protein involved in growth and survival. Crocidolite, amosite and chrysotile all reduced the receptor's "switched on" (phosphorylated) state in A549 cells. Crocidolite and amosite, listed as 27% iron by weight versus 2% for chrysotile, had a significantly greater effect. In A549 cells the effect increased with crocidolite dose and time; the other two cell types responded similarly to increasing doses. In A549 cells exposed for 3 to 24 hours, the receptor showed no apparent breakdown. In A549 cells, titanium dioxide particles did not change the receptor's phosphorylation. Blocking fiber uptake reduced the effect without fully preventing it. Fibers from which iron had been removed with desferrioxamine B caused much less of the effect. Treating cells with another iron chelator, phytic acid, also reduced it, to a lesser extent. The authors concluded that the effect appeared due, at least in part, to iron associated with the fibers, and to occur inside cells.

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) experiment on cultured human cell lines and primary human cells
• Who was studied: Human lung epithelial cells (A549, originally from an alveolar carcinoma), human pleural mesothelial cells (MET5A), and primary normal human small airway epithelial cells (SAEC). No human subjects.
• Exposure: Crocidolite, amosite, and chrysotile (short and intermediate range) at 6 micrograms per square centimeter for 24 h. Crocidolite was also tested at 1.5, 3, and 6 micrograms per square centimeter and for 15 min to 24 h. Comparisons were titanium dioxide (TiO2) particles and epidermal growth factor (EGF) as a positive control.
• Main results:
  • In A549 cells, all three asbestos types significantly decreased the background (constitutive) phosphorylation of EGFR at sites Y1068 and Y1173.
  • The size of the decrease appeared related to the iron content of the fibers (27%, 27% and 2% iron by weight for crocidolite, amosite and chrysotile) and to the amount of iron mobilized from them. Crocidolite and amosite caused significantly more dephosphorylation than chrysotile.
  • In A549 cells, crocidolite-induced EGFR dephosphorylation occurred within the first 3 h. The peak response was at 24 h, with almost total disappearance of phosphorylation bands.
  • In A549 cells, crocidolite at 1.5, 3, or 6 micrograms per square centimeter reduced EGFR kinase activity on a test substrate below control levels by 2- to 4-fold, in a dose-dependent manner.
  • In 24-hour dose experiments, MET5A mesothelial cells and normal small airway epithelial cells responded to crocidolite in a similar way to A549 cells.
  • In A549 cells, crocidolite also decreased phosphorylation of the related receptor HER2 at Y877 and Y1248, with a minor, time-dependent decrease in total HER2 protein.
  • In A549 cells, TiO2 particles had no effect on the EGFR phosphorylation state.
  • In A549 cells, crocidolite exposure for 3 to 24 h caused negligible Y1045 phosphorylation and no apparent decrease in surface EGFR. The authors concluded the receptor was not degraded.
  • Blocking fiber uptake with cytochalasin B or D considerably inhibited the crocidolite-induced dephosphorylation of EGFR. Receptor phosphorylation did not fully recover.
  • Crocidolite fibers from which iron had been removed with desferrioxamine B before exposure caused much less EGFR dephosphorylation.
  • Pretreating cells with the iron chelator phytic acid also reduced crocidolite-induced EGFR dephosphorylation, but to a lesser extent than desferrioxamine B pretreatment of the fibers. Phytic acid alone had no effect.
• The authors' conclusion: The authors concluded that crocidolite caused EGFR dephosphorylation and inactivation in A549, MET5A and SAEC cells. They concluded that this appeared to be mediated at least in part by bioavailable iron and to occur inside the cells. They suggested that EGFR inactivation may be a step in the pathway to apoptosis (cell death).
• Limitations the authors state:
  • The authors state that the main mechanism by which iron from asbestos leads to receptor inactivation is not yet clear.
  • The authors note concern that A549 cells, derived from a carcinoma, may not faithfully represent normal cells. They report that A549 cells responded like normal SAEC cells in this study.

Topics

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

Medical terms in this study, explained in our Lexicon: EGFR, A549 Cells, Crocidolite, HER2, Desferrioxamine B, Amosite, Chrysotile.

Related studies

• Increased expression of epidermal growth factor receptor in rat pleural mesothelial cells correlates with carcinogenicity of mineral fibres — S.P. Faux, C.E. Houghton, et al. (2000)
• Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis — C.L. Zanella, C.R. Timblin, et al. (1999)
• Increased epidermal growth factor-receptor protein in a human mesothelial cell line in response to long asbestos fibers — J.C. Pache, Y.M. Janssen, et al. (1998)
• Repetitive dissociation from crocidolite asbestos acts as persistent signal for epidermal growth factor receptor — E.S. Taylor, A.G. Wylie, et al. (2013)
• Epidermal growth factor receptor mutations in 510 Finnish non--small-cell lung cancer patients — S. Mäki-Nevala, M. Rönty, et al. (2014)
• Stability of mineral fibres in contact with human cell cultures. An in situ μXANES, μXRD and XRF iron mapping study — S. Pollastri, A.F. Gualtieri, et al. (2016)

Browse more research in American Journal of Respiratory Cell and Molecular Biology, or return to medical research.