Molecular Activation of Activator Protein-1 In Silica and Asbestos-Induced Carcinogenesis

Our plain-English summary of Molecular Activation of Activator Protein-1 In Silica and Asbestos-Induced Carcinogenesis, by V. Vallyathan, M. Ding, X. Shi, et al (Inhalation Toxicology, 2000).

The study

• Authors: V. Vallyathan, M. Ding, X. Shi, V. Castranova
• Journal: Inhalation Toxicology
• Published: 2000;12 Suppl 3:353-7
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Occupational exposures to asbestos and crystalline silica have been implicated in causing lung cancer and other pulmonary diseases in humans. Despite intensive research during the last decade on pulmonary carcinogenesis induced by these minerals, the exact molecular mechanisms involved in carcinogenesis are still unknown. Chronic inflammation and enhanced production of reactive oxygen species (ROS) generated by these particulates have been implicated in the development of tumors. In an attempt to understand the molecular basis of carcinogenesis induced by these particles, we investigated the potential activation of activator protein-1 (AP-1) by crocidolite and freshly fractured or aged crystalline silica in a JB6 P(+) cell line stably transfected with AP-1-luciferase reporter plasmid (in vitro) and in AP-1-luciferase reporter transgenic mice (in vivo). This transcription factor governs the expression of target genes that are involved in encoding cytokines, chemokines, growth factors, cell adhesion molecules, and acute-phase proteins that regulate inflammation, cell proliferation, and apoptosis. Results of our studies suggest that asbestos and silica activate AP-1 through generation of ROS. In in vitro studies, crocidolite asbestos caused a dose- and time-dependent AP-1 activation in JB6+ cells, which persisted for at least 72 h. In transgenic mice exposed to crocidolite asbestos, AP-1 activation increased significantly by 10-fold in lung tissue and 22-fold in bronchial tissue. This induction of AP-1 activation by crocidolite appears to be mediated through the influence of mitogen-activated protein kinase (MAPK) family members, specifically extracellular signal-regulating protein kinase, ERK 1, and ERK 2 (data not presented). Similarly, freshly fractured silica caused an 8-fold increase in AP-1 activation in JB6 P+cells and 22-fold increase in transgenic mice. The activation of AP-1 by freshly fractured silica was mediated through ERK1, ERK2, and p38 kinase. Activation of AP-1 by asbestos or silica was inhibited in both in vitro and in vivo systems by aspirin, which exhibits OH radical scavenging properties. It is proposed from these studies that asbestos and crystalline silica may promote carcinogenesis through specific mechanistic pathways stimulated by ROS.

In plain English

This short supplement paper reported the authors' laboratory experiments on activation of the transcription factor activator protein-1 (AP-1) by crocidolite asbestos and crystalline silica. Experiments used JB6 P+ mouse epidermal cells with an AP-1-luciferase reporter plasmid in vitro and AP-1-luciferase reporter transgenic mice given particles intratracheally. In the cells, activation was significant after 24 h with 80 micrograms per millilitre freshly fractured silica and with 2.5 micrograms per millilitre crocidolite, peaking at 7.5 micrograms per millilitre; freshly fractured silica was more potent than aged silica. The figure's eightfold silica and twofold crocidolite increases came from unmatched conditions (200 micrograms per millilitre silica, 24 h; 7.5 micrograms per millilitre crocidolite, 36 h), a difference the authors linked partly to the higher silica dose. In mice, crocidolite raised AP-1 induction 10-fold in lung and 22-fold in bronchiolar tissue; silica 22-fold in whole lung. Aspirin, a hydroxyl-radical scavenger, inhibited the silica response in vitro by 90 percent and the crocidolite response in mice by 89 percent. The authors proposed these minerals may promote carcinogenesis through reactive oxygen species.

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: Experimental laboratory study combining in vitro cell-culture work and in vivo transgenic mouse experiments, presented as a short summary of the authors' own published studies
• Who was studied: JB6 P+ mouse epidermal cells transfected with an AP-1-luciferase reporter plasmid, and transgenic mice (C57Bl/6 males carrying the TRE-luciferase transgene crossed with DBA2 females); at least eight determinations per cell condition and at least eight animals per group
• Exposure: Crocidolite asbestos and crystalline silica (freshly fractured or aged); cells exposed to silica 200 micrograms per millilitre for 24 h or crocidolite 7.5 micrograms per millilitre for 36 h; mice given 5 mg silica or 100 micrograms crocidolite by intratracheal instillation
• Main results:
  • In JB6 P+ cells, significant AP-1 activation occurred after 24 h with 80 micrograms per millilitre freshly fractured silica, and freshly fractured silica activated AP-1 more than aged silica
  • In JB6 P+ cells, significant AP-1 activation occurred at 2.5 micrograms per millilitre crocidolite, peaked at 7.5 micrograms per millilitre, was maximal at 36 h and remained elevated at 72 h
  • In the cell system, silica (200 micrograms per millilitre, 24 h) produced an eightfold increase in AP-1 activation versus a twofold increase with crocidolite (7.5 micrograms per millilitre, 36 h); the authors suggested this may relate to different activation pathways and the higher silica dose used
  • In transgenic mice, crocidolite increased AP-1 induction 10-fold in lung tissue and 22-fold in bronchiolar tissue, and silica increased it 22-fold in whole lung tissue
  • In the cells, aspirin inhibited the freshly fractured silica response by 90 percent and completely inhibited the crocidolite response
  • In transgenic mice, aspirin 120 mg/kg intraperitoneally before and after crocidolite instillation inhibited AP-1 activation by 89 percent
• The authors' conclusion: The authors proposed that the carcinogenic effect of crocidolite asbestos and crystalline silica may be mediated through generation of hydroxyl radicals leading to AP-1 activation, and suggested these minerals can promote molecular events linked to carcinogenesis independently of confounders such as tobacco smoke

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Occupational Exposure, Crystalline, Lung Cancer, Chronic Inflammation, Reactive Oxygen Species (ROS), Crocidolite, Cytokine.

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