title: The iron component of particulate matter is antiapoptotic: A clue to the development of lung cancer after exposure to atmospheric pollutants?
abstract: The classification of outdoor air pollution as carcinogenic for humans strengthens the increasing concern about particulate matter (PM). We previously demonstrated that PM exposure produces an antiapoptotic effect resulting from polycyclic aromatic hydrocarbons (PAH) and water-soluble components. In this study, we investigated transition metallic compounds, particularly iron, in order to decipher their underlying molecular mechanisms that prevent apoptosis. Human bronchial epithelial cells were exposed for 4 h to different PM samples with established antiapoptotic effect (e.g. PM-AW) or not (e.g. PM-VS) or to their metallic components (Fe, Mn, Zn and Al) before apoptosis induction by the calcium ionophore A23187 or Staurosporine. PM-AW, Fe, Mn and Al significantly reduced induced apoptosis. The antiapoptotic effect of Fe was enhanced by benzo(a)pyrene, a typical PAH compound, but was totally reversed by the iron chelator, deferiprone. Furthermore, particles and iron triggered cellular ROS generation and prevented the depletion in glutathione levels observed during A23187-induced apoptosis. In contrast to benzo(a)pyrene, PM-AW and Fe rapidly activated NRF2, subsequently upregulated several target genes (HO1, NQO1 and GPX1) and modulated some genes which control cell death (BCL2, BAX and p53). The key role of the NRF2 pathway in the antiapoptotic effect mediated by Fe and PM was demonstrated using siRNA technology. Our results suggest that the iron component participates in the antiapoptotic effect of PM by activating a NRF2-dependent antioxidant process. As resisting to cell death is one of the hallmarks of cancer cells, these findings provide additional clues for understanding the development of lung cancer after atmospheric pollution exposure.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Unit of Functional and Adaptive Biology, CNRS UMR 8251, Paris, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Lovera-Leroux
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Unit of Functional and Adaptive Biology, CNRS UMR 8251, Paris, France.
authors.forename: Belinda
authors.initials: B
authors.lastname: Crobeddu
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Unit of Functional and Adaptive Biology, CNRS UMR 8251, Paris, France.
authors.forename: Nadim
authors.initials: N
authors.lastname: Kassis
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR-S 1124, Paris, France.
authors.forename: Patrice X
authors.initials: PX
authors.lastname: Petit
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Unit of Functional and Adaptive Biology, CNRS UMR 8251, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Unit of Functional and Adaptive Biology, CNRS UMR 8251, Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Baeza-Squiban
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Unit of Functional and Adaptive Biology, CNRS UMR 8251, Paris, France. Electronic address: karine.andreau@univ-paris-diderot.fr.
authors.forename: Karine
authors.initials: K
authors.lastname: Andreau
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007501:Iron / Q000633:toxicity*; D008175:Lung Neoplasms / Q000209:etiology*; D018613:Microscopy, Confocal; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D052638:Particulate Matter / Q000633:toxicity*; D017382:Reactive Oxygen Species; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D052638:Particulate Matter; D017382:Reactive Oxygen Species; D007501:Iron
keywords: A23187; Airborne particles; Bronchial epithelial cells; Cell death; Oxidative stress; Transition metal