RRC ID 60799
Author Ito F, Yanatori I, Maeda Y, Nimura K, Ito S, Hirayama T, Nagasawa H, Kohyama N, Okazaki Y, Akatsuka S, Toyokuni S.
Title Asbestos conceives Fe(II)-dependent mutagenic stromal milieu through ceaseless macrophage ferroptosis and β-catenin induction in mesothelium.
Journal Redox Biol
Abstract Asbestos is still a social burden worldwide as a carcinogen causing malignant mesothelioma. Whereas recent studies suggest that local iron reduction is a preventive strategy against carcinogenesis, little is known regarding the cellular and molecular mechanisms surrounding excess iron. Here by differentially using high-risk and low-risk asbestos fibers (crocidolite and anthophyllite, respectively), we identified asbestos-induced mutagenic milieu for mesothelial cells. Rat and cell experiments revealed that phagocytosis of asbestos by macrophages results in their distinctive necrotic death; initially lysosome-depenent cell death and later ferroptosis, which increase intra- and extra-cellular catalytic Fe(II). DNA damage in mesothelial cells, as assessed by 8-hydroxy-2'-deoxyguanosine and γ-H2AX, increased after crocidolite exposure during regeneration accompanied by β-catenin activation. Conversely, β-catenin overexpression in mesothelial cells induced higher intracellular catalytic Fe(II) with increased G2/M cell-cycle fraction, when p16INK4A genomic loci localized more peripherally in the nucleus. Mesothelial cells after challenge of H2O2 under β-catenin overexpression presented low p16INK4A expression with a high incidence of deletion in p16INK4A locus. Thus, crocidolite generated catalytic Fe(II)-rich mutagenic environment for mesothelial cells by necrotizing macrophages with lysosomal cell death and ferroptosis. These results suggest novel molecular strategies to prevent mesothelial carcinogenesis after asbestos exposure.
Volume 36
Pages 101616
Published 2020-9-1
DOI 10.1016/j.redox.2020.101616
PII S2213-2317(20)30821-1
PMID 32863225
PMC PMC7330611
MeSH Animals Asbestos* Epithelium Ferroptosis* Ferrous Compounds Hydrogen Peroxide Macrophages Mesothelioma* Mutagens Rats beta Catenin / genetics
IF 9.986
DNA material pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)
Human and Animal Cells 293T(RCB2202)