Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912.
Toxicol Sci. 2013 Dec;136(2):467-77. doi: 10.1093/toxsci/kft214. Epub 2013 Sep 25.
Cobalt(II) and nickel(II) ions display similar chemical properties and act as hypoxia mimics in cells. However, only soluble Co(II) but not soluble Ni(II) is carcinogenic by inhalation. To explore potential reasons for these differences, we examined responses of human lung cells to both metals. We found that Co(II) showed almost 8 times higher accumulation than Ni(II) in H460 cells but caused a less efficient activation of the transcriptional factor p53 as measured by its accumulation, Ser15 phosphorylation, and target gene expression. Unlike Ni(II), Co(II) was ineffective in downregulating the p53 inhibitor MDM4 (HDMX). Co(II)-treated cells continued DNA replication at internal doses that caused massive apoptosis by Ni(II). Apoptosis and the overall cell death by Co(II) were delayed and weaker than by Ni(II). Inhibition of caspases but not programmed necrosis pathways suppressed Co(II)-induced cell death. Knockdown of p53 produced 50%-60% decreases in activation of caspases 3/7 and expression of 2 most highly upregulated proapoptotic genes PUMA and NOXA by Co(II). Overall, p53-mediated apoptosis accounted for 55% cell death by Co(II), p53-independent apoptosis for 20%, and p53/caspase-independent mechanisms for 25%. Similar to H460, normal human lung fibroblasts and primary human bronchial epithelial cells had several times higher accumulation of Co(II) than Ni(II) and showed a delayed and weaker caspase activation by Co(II). Thus, carcinogenicity of soluble Co(II) could be related to high survival of metal-loaded cells, which permits accumulation of genetic and epigenetic abnormalities. High cytotoxicity of soluble Ni(II) causes early elimination of damaged cells and is expected to be cancer suppressive.
钴(II)和镍(II)离子具有相似的化学性质，在细胞中充当缺氧模拟物。然而，只有可溶的 Co(II)而不是可溶的 Ni(II)通过吸入致癌。为了探讨这些差异的潜在原因，我们研究了两种金属对人肺细胞的反应。我们发现，Co(II)在 H460 细胞中的积累几乎是 Ni(II)的 8 倍，但作为转录因子 p53 的激活效率较低，其积累、Ser15 磷酸化和靶基因表达均如此。与 Ni(II)不同，Co(II)不能有效下调 p53 抑制剂 MDM4 (HDMX)。Co(II)处理的细胞继续进行 DNA 复制，导致大量凋亡的内部剂量由 Ni(II)引起。与 Ni(II)相比，Co(II)诱导的细胞凋亡和总细胞死亡延迟且较弱。细胞凋亡抑制剂但不是程序性坏死途径抑制了 Co(II)诱导的细胞死亡。p53 敲低导致 Co(II)激活 caspase 3/7 和表达 2 个上调最明显的促凋亡基因 PUMA 和 NOXA 减少 50%-60%。总的来说，p53 介导的细胞凋亡占 Co(II)诱导的细胞死亡的 55%，p53 非依赖性细胞凋亡占 20%，p53/caspase 非依赖性机制占 25%。与 H460 相似，正常的人肺成纤维细胞和原代人支气管上皮细胞对 Co(II)的积累是 Ni(II)的数倍，Co(II)引起的 caspase 激活延迟且较弱。因此，可溶性 Co(II)的致癌性可能与金属负载细胞的高存活率有关，这允许遗传和表观遗传异常的积累。可溶性 Ni(II)的高细胞毒性导致受损细胞的早期消除，预计具有抗癌作用。
