Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis

Our plain-English summary of Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis, by C.L. Zanella, C.R. Timblin, A. Cummins, et al (The American Journal of Physiology, 1999).

The study

• Authors: C.L. Zanella, C.R. Timblin, A. Cummins, M. Jung, J. Goldberg, R. Raabe, T.R. Tritton, B.T. Mossman
• Journal: The American Journal of Physiology
• Published: 1999;277(4):L684-93
• Cited by: 74 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

We examined the mechanisms of interaction of crocidolite asbestos fibers with the epidermal growth factor (EGF) receptor (EGFR) and the role of the EGFR-extracellular signal-regulated kinase (ERK) signaling pathway in early-response protooncogene (c-fos/c-jun) expression and apoptosis induced by asbestos in rat pleural mesothelial (RPM) cells. Asbestos fibers, but not the nonfibrous analog riebeckite, abolished binding of EGF to the EGFR. This was not due to a direct interaction of fibers with ligand, inasmuch as binding studies using fibers and EGF in the absence of membranes showed that EGF did not adsorb to the surface of asbestos fibers. Exposure of RPM cells to asbestos caused a greater than twofold increase in steady-state message and protein levels of EGFR (P < 0.05). The tyrphostin AG-1478, which inhibits the tyrosine kinase activity of the EGFR, but not the tyrphostin A-10, which does not affect EGFR activity, significantly ameliorated asbestos-induced increases in mRNA levels of c-fos but not of c-jun. Pretreatment of RPM cells with AG-1478 significantly reduced apoptosis in cells exposed to asbestos. Our findings suggest that asbestos-induced binding to EGFR initiates signaling pathways responsible for increased expression of the protooncogene c-fos and the development of apoptosis. The ability to block asbestos-induced elevations in c-fos mRNA levels and apoptosis by small-molecule inhibitors of EGFR phosphorylation may have therapeutic implications in asbestos-related diseases.

In plain English

This was a laboratory study of cells taken from the pleura (the lining around the lungs) of Fischer 344 rats and grown in dishes. The authors exposed these rat pleural mesothelial cells to crocidolite asbestos fibers or to riebeckite, a nonfibrous mineral chemically similar to crocidolite. They studied the epidermal growth factor receptor (EGFR), a protein on the cell surface. Crocidolite, but not riebeckite, blocked epidermal growth factor from binding to the receptor, and the growth factor did not stick to the fibers themselves. Asbestos raised the cells' EGFR message and protein levels more than twofold. A drug that blocks EGFR activity, AG-1478, significantly reduced the asbestos-induced rise in c-fos, a protooncogene, but not the rise in c-jun. A comparison drug, A-10, had no effect on c-fos. Asbestos-induced cell death (apoptosis) rose with dose and over time. AG-1478 significantly reduced it after 24 and 48 hours of exposure, while A-10 did not. The authors concluded that their findings suggest asbestos acting on EGFR starts signaling linked to c-fos and apoptosis, which may have therapeutic implications.

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 rat cells
• Who was studied: rat pleural mesothelial (RPM) cells isolated from the parietal pleura of Fischer 344 rats and grown in culture (University of Vermont); no human subjects
• Exposure: NIEHS-processed crocidolite asbestos fibers from the Thermal Insulation Manufacturers Association fiber repository, or nonfibrous riebeckite, at 2.5 to 10.0 µg/cm2 of culture dish. Some cells were pretreated with the tyrphostins AG-1478 (0.1, 1 and 10 µM; blocks EGFR) or A-10 (10 µM; does not affect EGFR). EGF and TPA were used as comparison agents.
• Main results:
  • Crocidolite asbestos blocked binding of labeled EGF to RPM cell membrane preparations; riebeckite did not.
  • In tests without cell membranes, EGF did not bind to or adsorb onto crocidolite or riebeckite particles.
  • Asbestos exposure of RPM cells caused a greater than twofold increase in EGFR message and protein levels (P less than 0.05).
  • Increases in EGFR mRNA with crocidolite at 5 µg/cm2 appeared at 8 h. They were not seen at 10 µg/cm2, which the authors attributed to that dose killing cells.
  • Unlike EGF, asbestos exposure for up to 8 h did not cause breakdown of existing EGFR.
  • AG-1478 at 0.1 to 10 µM blocked EGF-stimulated ERK activity in RPM cells; A-10 (10 µM) did not.
  • Pretreatment with 10 µM AG-1478 significantly (P less than 0.05) reduced the asbestos-induced increase in c-fos mRNA; A-10 had no effect.
  • Neither AG-1478 nor A-10 reduced the asbestos-induced increase in c-jun mRNA.
  • Apoptosis in response to asbestos was dose dependent and increased over time. Pretreatment with 10 µM AG-1478 significantly reduced the number of apoptotic cells after 24 and 48 h of asbestos exposure.
  • In Table 1, the 48 h crocidolite 5 µg/cm2 row is printed as '42.0063.21' without AG-1478 and '28.9362.79' with AG-1478. Read as mean plus or minus SE in percent apoptotic cells, this is 42.00 plus or minus 3.21 without the drug and 28.93 plus or minus 2.79 with it (significant reduction). That reading rests on the table note 'Values are means 6 SE', where 6 stands for plus or minus.
  • In Table 1, the 48 h crocidolite 10 µg/cm2 row is printed as '49.8460.91' without AG-1478 and '43.5860.13' with AG-1478. Read the same way, this is 49.84 plus or minus 0.91 percent and 43.58 plus or minus 0.13 percent apoptotic cells (significant reduction).
  • Pretreatment with A-10 did not reduce apoptosis from crocidolite (5 µg/cm2) at 48 h.
• The authors' conclusion: The authors concluded that their findings suggest asbestos sets off a chain of cell signaling events in mesothelial cells that can be interrupted by inhibiting EGFR phosphorylation. They also suggested that blocking these events with small-molecule EGFR inhibitors may have therapeutic implications in asbestos-related diseases.
• Limitations the authors state:
  • The authors state that the exact nature of the interaction between asbestos fibers and EGFR remains undetermined.
  • AG-1478 did not completely block the asbestos-induced rise in c-fos, which the authors suggest may reflect other activating factors downstream of EGFR.

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, EGFR, Riebeckite.

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)
• Patterns of c-fos and c-jun proto-oncogene expression, apoptosis, and proliferation in rat pleural mesothelial cells exposed to erionite or asbestos fibers — C.R. Timblin, G.D. Guthrie, et al. (1998)
• Role of iron in inactivation of epidermal growth factor receptor after asbestos treatment of human lung and pleural target cells — A. Baldys, A.E. Aust (2005)
• Repetitive dissociation from crocidolite asbestos acts as persistent signal for epidermal growth factor receptor — E.S. Taylor, A.G. Wylie, et al. (2013)
• 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)
• Novel cell imaging techniques show induction of apoptosis and proliferation in mesothelial cells by asbestos — J.L. Goldberg, C.L. Zanella, et al. (1997)

Browse more research in The American Journal of Physiology, or return to medical research.