| 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
|
| Resource |
| DNA material |
pCMV-VSV-G-RSV-Rev (RDB04393)
pCAG-HIVgp (RDB04394) |
| Human and Animal Cells |
293T(RCB2202)
RAW 264(RCB0535)
THP-1(RCB1189) |
