Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu, 501-1196, Japan.
Redox Biol. 2020 Sep;36:101616. doi: 10.1016/j.redox.2020.101616. Epub 2020 Jun 24.
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 p16 genomic loci localized more peripherally in the nucleus. Mesothelial cells after challenge of HO under β-catenin overexpression presented low p16 expression with a high incidence of deletion in p16 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.
石棉仍然是一种致癌物质，会导致恶性间皮瘤，这是全球范围内的社会负担。尽管最近的研究表明局部铁还原是预防致癌作用的一种策略，但对于过量铁周围的细胞和分子机制知之甚少。在这里，我们通过差异使用高风险和低风险的石棉纤维（青石棉和透闪石），确定了石棉诱导的间皮细胞致突变环境。大鼠和细胞实验表明，巨噬细胞吞噬石棉会导致其独特的坏死性死亡；最初是溶酶体依赖性细胞死亡，后来是铁死亡，这会增加细胞内和细胞外的催化 Fe(II)。在用青石棉进行再生时，通过 8-羟基-2'-脱氧鸟苷和 γ-H2AX 评估间皮细胞中的 DNA 损伤增加，同时伴有β-连环蛋白的激活。相反，当 p16 基因组位于核内更外周时，β-连环蛋白在间皮细胞中的过度表达会导致更高的细胞内催化 Fe(II)和更高的 G2/M 细胞周期分数。在β-连环蛋白过表达的情况下，HO 对间皮细胞的挑战导致低水平的 p16 表达和 p16 基因座缺失的高发生率。因此，青石棉通过溶酶体细胞死亡和铁死亡使巨噬细胞坏死，产生富含催化 Fe(II)的致突变环境，从而导致间皮细胞癌变。这些结果表明了在石棉暴露后预防间皮细胞癌变的新的分子策略。
