Asbestos conceives Fe(II)-dependent mutagenic stromal milieu through ceaseless macrophage ferroptosis and β-catenin induction in mesothelium
Asbestos conceives Fe(II)-dependent mutagenic stromal milieu through ceaseless macrophage ferroptosis and β-catenin induction in mesothelium
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DOI：
10.1016/j.redox.2020.101616
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发表时间：
2020-09-01
期刊：
影响因子：
11.4
通讯作者：
Toyokuni, Shinya
中科院分区：
文献类型：
--
作者：
Ito, Fumiya;Yanatori, Izumi;Toyokuni, Shinya
石棉仍然是世界范围内的社会负担，因为它是一种致癌物质，会导致恶性间皮瘤。虽然最近的研究表明，局部减少铁是一种预防癌症发生的策略，但对围绕过量铁的细胞和分子机制知之甚少。在这里，通过不同地使用高风险和低风险的石棉纤维(分别是青石棉和叶绿石)，我们确定了石棉诱导间皮细胞的诱变环境。大鼠和细胞实验表明，巨噬细胞吞噬石棉导致其独特的坏死性死亡；最初依赖溶酶体的细胞死亡，后来铁下垂，这增加了细胞内和细胞外的催化Fe(II)。间皮细胞DNA损伤由8-羟基-2‘-脱氧鸟苷和伽马-H_2AX评估，在伴随β-连环蛋白激活的再生过程中，青石棉暴露后细胞DNA损伤增加。相反，当p16(INK4A)基因组定位于细胞核更外围时，间皮细胞中β-连环素的过度表达导致更高的细胞内催化铁(II)和增加的G2/M细胞周期比例。H_2O_2刺激后的间皮细胞在β-连环蛋白过表达的情况下，p16(INK4A)基因低表达，p16(INK4A)基因缺失率高。因此，青石棉通过使巨噬细胞坏死、溶酶体细胞死亡和酵母菌下垂，为间皮细胞产生富Fe(II)的催化诱变环境。这些结果提示了新的分子策略，以防止石棉暴露后间皮癌的发生。
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 gamma-H2AX, increased after crocidolite exposure during regeneration accompanied by beta-catenin activation. Conversely, beta-catenin overexpression in mesothelial cells induced higher intracellular catalytic Fe(II) with increased G2/M cell-cycle fraction, when p16(INK4A) genomic loci localized more peripherally in the nucleus. Mesothelial cells after challenge of H2O2 under beta-catenin overexpression presented low p16(INK4A) expression with a high incidence of deletion in p16(INK4A) locus. Thus, crocidolite generated catalytic Fe(II)-rich mutagenic environment for mesothelial cells by necrotizing macrophages with lysosomal cell death and fermptosis. These results suggest novel molecular strategies to prevent mesothelial carcinogenesis after asbestos exposure.